Benzothiophene derivatives, their preparation and use as urokinase inhibitors

ABSTRACT

A compound of the formula ##STR1## in which R 1  is hydrogen, lower alkyl, optionally substituted ar(lower)alkyl, cyclo(lower)alkyl(lower)alkyl, protected carboxy)lower)alkyl, carboxy)lower)alkyl, hydroxy(lower)alkyl, optionally substituted lower alkylcarbamoyl(lower)alkyl, lower alkylthio(lower)alkyl, carboxy(lower)alkanoyl, protected carboxy(lower)alkanoyl, aroyl, lower alkanoyl, or optionally substituted arylcarbamoyl(lower)alkyl, 
     R 2  is hydrogen, carboxy, protected carboxy, formyl or N-(lower)alkyl-N-(lower)alkoxycarbamoyl, 
     R 3  is hydrogen or amidino-protective group, 
     A is lower alkylene or carbonyl, 
     X is ##STR2## Y is --S-- or --SO 2  --, Z is --S-- or --O--, 
     or pharmaceutically acceptable salts thereof 
     which is useful as a medicament.

This is a National Stage Application of International Application No.PCT/JP97/03215, filed Sep. 12, 1997.

TECHNICAL FIELD

The present invention relates to novel compounds and pharmaceuticallyacceptable salts thereof.

More particularly, it relates to novel amidino derivatives andpharmaceutically acceptable salts thereof, which are useful as urokinaseinhibitors, to processes for the preparation thereof, to apharmaceutical composition comprising the same, to a use of the same asa medicament and to a method of the therapeutic treatment of diseases ina human being or an animal.

Accordingly, one object of the present invention is to provide novelamidino derivatives and pharmaceutically acceptable salts thereof, whichare useful as urokinase inhibitors.

Another object of the present invention is to provide processes for thepreparation of novel amidino derivatives and salts thereof.

A further object of the present invention is to provide a pharmaceuticalcomposition comprising, as an active ingredient, said amidinoderivatives and pharmaceutically acceptable salts thereof.

Urokinase (urokinase-type Plasminogen Activator, uPA) is a multi-domainserine protease which is able to convert the inactive precursorplasminogen to active plasmine.

Among the family of plasminogen activators, tissue type plasminogenactivator (tPA) is present both in normal and in malignant tissue,whereas uPA has been shown to be produced abundantly by several commonmalignancies such as melanoma and colon, breast and prostate cancers.

Cellular invasiveness initiated by urokinase causes many physiologicalprocesses such as angiogenesis, neovascularization, bone restructuring,embryo implantation in the uterus (embryonic development), infiltrationof immune cells into inflammatory sites, ovulation, trophoblastimplantation, breast, uterine, and prostatic involution,spermatogenesis, tissue remodeling during wound repair (wound healing)and organ differentiation, fibrosis, local invasion of tumors intoadjacent areas (tumor invasion), metastatic spread of tumor cells fromprimary to secondary sites (tumor metastasis), and tissue destruction inarthritis.

Inhibitors of urokinase therefore have mechanism-based anti-angiogenic,anti-arthritic, anti-inflammatory, anti-invasive, anti-metastatic,anti-osteoporotic, anti-retinopathic (for angiogenesis-dependentretinopathies), contraceptive, and tumoristatic activities.

DISCLOSURE OF INVENTION

The object amidino derivatives are novel and can be represented by thefollowing general formula: ##STR3## in which R¹ is hydrogen, optionallysubstituted lower alkylcarbamoyl(lower)alkylidene, lower alkylidene,lower alkyl, optionally substituted ar(lower)alkyl,cyclo(lower)alkyl(lower)alkyl, protected carboxy(lower)alkyl,carboxy(lower)alkyl, hydroxy(lower)alkyl, optionally substituted loweralkylcarbamoyl(lower)alkyl, lower alkylthio(lower)alkyl,carboxy(lower)alkanoyl, protected carboxy(lower)alkanoyl, aroyl, loweralkanoyl, or optionally substituted arylcarbamoyl(lower)alkyl,

R² is hydrogen, carboxy, protected carboxy, formyl orN-(lower)alkyl-N-(lower)alkoxycarbamoyl,

R³ is hydrogen or amidino-protective group,

A is lower alkylene or carbonyl,

X is ##STR4## Y is lower alkylene, --S-- or --SO₂ --, Z is --S-- or--O--, and the line: ##STR5## is a single bond or double bond, orpharmaceutically acceptable salts thereof.

Suitable salts of the object compound (I) are pharmaceuticallyacceptable, conventional non-toxic salts and may include;

a salt with a base such as an inorganic base salt, for example, analkali metal salt (e.g. sodium salt, potassium salt, etc.), an alkalineearth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammoniumsalt, an organic base salt, for example, an organic amine salt (e.g.triethylamine salt, pyridine salt, picoline salt, ethanolamine salt,triethanolamine salt, dicyclohexylamine salt,N,N'-dibenzylethylenediamine salt, etc.);

a salt with an acid such as inorganic acid addition salt (e.g.hydrochloride, hydrobromide, sulfate, phosphate, etc.), an organic acidaddition salt (e.g. formate, acetate, trifluoroacetate, maleate,tartrate, fumarate, methanesulfonate, benzenesulfonate, etc.);

a salt with a basic or acidic amino acid (e.g. arginine, aspartic acid,glutamic acid, etc.); and the like.

The object compound (I) and pharmaceutically acceptable salt thereof mayinclude a solvate [e.g. enclosure compound (e.g., hydrate, etc.)].

It is to be noted that the compound (I) and the other compounds mayinclude one or more stereoisomers due to asymmetric carbon atoms, andall of such Isomers and mixture thereof are included within the scope ofthis invention.

According to the present invention, the object compound (I) orpharmaceutically acceptable salts thereof can be prepared by theprocesses as illustrated by the following reaction schemes. ##STR6## inwhich R¹, R², R³, A, X, Y, Z and the line: ##STR7## are each as definedabove, R_(a) ¹ is optionally substituted loweralkylcarbamoyl(lower)alkylidene or lower alkylidene,

R_(b) ¹ is optionally substituted lower alkylcarbamoyl-(lower)alkyl orlower alkyl,

R_(c) ¹ is protected carboxy(lower)alkyl or protectedcarboxy(lower)alkanoyl,

R_(d) ¹ is carboxy(lower)alkyl or carboxy(lower)alkanoyl,

R_(a) ² is protected carboxy,

R_(b) ² is N-(lower)alkyl-N-(lower)alkoxycarbamoyl,

R_(a) ³ is amidino-protective group,

R⁴ is ester residue,

X_(a) is ##STR8##

The object compounds thus obtained can be converted to its salt by aconventional method.

The compound (II) used in the Process 1 may be new and can be prepared,for example, according to the following Preparations or by aconventional manner.

In the descriptions of the present specification, suitable examples andillustrations of the various definitions which the present inventionincludes within the scope thereof are explained in detail as follows.

The term "lower" is intended to mean 1 to 6 carbon atom(s), preferably 1to 4 carbon atom(s), unless otherwise indicated.

Suitable "lower alkoxy" may include straight or branched one such asmethoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentyloxy,hexyloxy, and the like, and the most preferable example may be methoxy.

Suitable "lower alkyl" may include straight or branched one such asmethyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, and thelike, and the most preferable example may be ethyl and butyl for R¹.

Suitable "ester residue" means a group substituted with the hydrogenatom in the "esterified carboxy" as mentioned below.

Suitable "optionally substituted arylcarbamoyl(lower)alkyl" meansaforementioned lower alkyl substituted by arylcarbamoyl group such asphenylcarbamoyl, tolylcarbamoyl, xylylcarbamoyl, cumenylcarbamoyl,mesitylcarbamoyl, naphthylcarbamoyl, and the like, and saidarylcarbamoyl group is optionally substituted by the group consisting oflower alkyl as mentioned above, lower alkoxy as mentioned above, andlower alkylenedioxy as mentioned below, in which more preferable examplemay be phenylcarbamoyl(lower)alkyl optionally substituted by loweralkylenedioxy, and the most preferable one may be3,4-methylenedioxyphenylcarbamoylmethyl.

Suitable "halogen" may include fluorine, bromine, chlorine and iodine,in which more preferable example may be fluorine.

Suitable "cyclo(lower)alkyl(lower)alkyl" means aforementioned loweralkyl substituted by cyclo(lower)alkyl as mentioned below, in which themost preferable example may be cyclohexylmethyl.

Suitable "optionally substituted ar(lower)alkyl" means aforementionedlower alkyl substituted by aryl as mentioned below, in which said arylgroup is optionally substituted by the group consisting of lower alkylas mentioned above, lower alkoxy as mentioned above, and loweralkylenedioxy as mentioned below, wherein more preferable example may beC₆ -C₁₀ ar(lower)alkyl optionally substituted by one or two suitablesubstituents selected from the group consisting of lower alkoxy andlower alkylenedioxy, and the most preferable one may be benzyl,phenethyl, 3,4-dimethoxyphenethyl and 3,4-methylenedioxyphenethyl.

Suitable "lower alkylenedioxy" may include straight or branched one suchas methylenedioxy, ethylenedioxy, trimethylenedioxy,tetramethylenedioxy, pentamethylenedioxy, hexamethylenedioxy,methylmethylenedioxy, ethylethylenedioxy, propylenedioxy, and the like,in which the most preferable one may be methylenedioxy.

Suitable "cyclo(lower)alkyl" may include cyclo(C₃ -C₆)-alkyl such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, in whichthe most preferable example may be cyclohexyl.

Preferable "aryl" may include C₆ -C₁₀ aryl such as phenyl, tolyl, xylyl,cumenyl, mesityl, naphthyl, etc., in which the most preferable one maybe phenyl.

Suitable "lower alkylidene" may include straight or branched one such asmethylene, ethylidene, propylidene, isopropylidene, butylidene,pentylidene, hexylidene, methylmethylidene, ethylethylidene,propylidene, and the like, in which the most preferred one may bebutylidene for R¹.

Suitable "optionally substituted lower alkylcarbamoyl(lower)alkylidene"means aforementioned lower alkylidene substituted by optionallysubstituted lower alkylcarbamoyl as mentioned below, wherein the mostpreferable example may be n-butylcarbamoylmethylidene.

Suitable "optionally substituted lower alkylcarbamoyl(lower)alkyl" meansaforementioned lower alkyl substituted by "optionally substituted loweralkylcarbamoyl" as mentioned below, wherein the most preferable examplemay be n-butylcarbamoylmethyl and 2,2,2-trifluoroethylcarbamoylmethyl.

Suitable "optionally substituted lower alkylcarbamoyl" may includecarbamoyl substituted by aforementioned lower alkyl, in which the loweralkyl group is optionally substituted by halogen as mentioned above, themost preferable one may be n-butylcarbamoyl and2,2,2-trifluoroethylcarbamoyl.

Suitable "hydroxy(lower)alkyl" may include straight or branched one suchas hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl,hydroxypentyl, hydroxyhexyl, and the like, in which the most preferableone may be 2-hydroxyethyl.

Suitable "lower alkylene" may include straight or branched one such asmethylene, ethylene, trimethylene, tetramethylene, pentamethylene,hexamethylene, methylmethylene, ethylethylene, propylene, and the like,en which the most preferable one may be methylene for A and Y, andethylene for Y.

Suitable "protected carboxy" may include esterified carboxy as mentionedbelow.

"Esterified carboxy" can be referred to the ones as mentioned below.

Suitable examples of the ester moiety of an esterified carboxy may bethe ones such as lower alkyl ester (e.g. methyl ester, ethyl ester,propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butylester, pentyl ester, hexyl ester, etc.) which may have at least onesuitable substituent(s) for example, lower alkanoyloxy(lower)alkyl ester[e.g. acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethylester, valeryloxymethyl ester, pivaloyloxymethyl ester,hexanoyloxymethyl ester, 1-(or 2-)acetoxyethyl ester, 1-(or 2- or3-)acetoxypropyl ester, 1-(or 2- or 3- or 4-)acetoxybutyl ester, 1-(or2-)-propionyloxyethyl ester, 1-(or 2- or 3-)propionyloxypropyl ester,1-(or 2-)butyryloxyethyl ester, 1-(or 2-)-isobutyryloxyethyl ester,1-(or 2-)-pivaloyloxyethyl ester, 1-(or 2-)hexanoyloxyethyl ester,isobutyryloxymethyl ester, 2-ethylbutyryloxymethyl ester,3,3-dimethylbutyryloxymethyl ester, 1-(or 2-)pentanoyloxyethyl ester,etc.], aroyl(lower)alkyl ester such as benzoyl(lower)alkyl ester (e.g.phenacyl ester, etc.), lower alkanesulfonyl(lower)alkyl ester (e.g.2-mesylethyl ester, etc.), mono(or di or tri)halo(lower)alkyl ester(e.g. 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.); loweralkoxycarbonyloxy(lower)alkyl ester [e.g. methoxycarbonyloxymethylester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester,t-butoxycarbonyloxymethyl ester, 1-(or 2-)methoxycarbonyloxyethyl ester,1-(or 2-)ethoxycarbonyloxyethyl ester, 1-(or2-)-isopropoxycarbonyloxyethyl ester, etc.], phthalidylidene(lower)alkylester, or (5-lower alkyl-2-oxo-1,3-dioxol-4-yl) (lower)alkyl ester [e.g.(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester,(5-ethyl-2-oxo-1,3-dioxol-4-yl)methyl ester,(5-propyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, etc.]; lower alkenyl ester(e.g. vinyl ester, allyl ester, etc.); lower alkynyl ester (e.g. ethynylester, propynyl ester, etc.); ar(lower)alkyl ester which may have atleast one suitable substituent(s) (e.g. benzyl ester, 4-methoxybenzylester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydrylester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester,4-hydroxy-3,5-di-t-butylbenzyl ester, etc.); aryl ester which may haveat least one suitable substituent(s) (e.g. phenyl ester, 4-chlorophenylester, tolyl ester, t-butylphenyl ester, xylyl ester, mesityl ester,cumenyl ester, etc.); phthalidyl ester; and the like.

Preferable examples of the protected carboxy thus defined may be loweralkoxycarbonyl.

Suitable "carboxy(lower)alkyl" means aforementioned lower alkyl which issubstituted by carboxy, wherein the preferable examples may becarboxymethyl.

Suitable "protected carboxy(lower)alkyl" means aforementioned loweralkyl which is substituted by above-mentioned "protected carboxy",wherein more preferable example may be lower alkoxycarbonyl(lower)alkyl,phenyl(lower)alkoxycarbonyl(lower)alkyl andbenzoyl(lower)alkoxycarbonyl(lower)alkyl, and the most preferable onemay be ethoxycarbonylmethyl and ethoxycarbonylpropyl.

Suitable "N-(lower)alkyl-N-(lower)alkoxycarbamoyl" means carbamoyl groupN-substituted by lower alkyl as mentioned above and also N-substitutedby lower alkoxy as mentioned above, in which more preferable example maybe N-(C₁ -C₄)-alkyl-N-(C₁ -C₄)alkoxycarbamoyl, and the most preferableone may be N-methyl-N-methoxycarbamoyl.

Suitable "amidino-protective group may include acyl.

Suitable "acyl" may include carbamoyl, aliphatic acyl group and acylgroup containing an aromatic ring, which is referred to as aromaticacyl, or heterocyclic ring, which is referred to as heterocyclic acyl.

Suitable example of said acyl may be illustrated as follows :

Carbamoyl; Thiocarbamoyl; Sulfamoyl; Aliphatic acyl such as lower orhigher alkanoyl (e.g., formyl, acetyl, propanoyl, butanoyl,2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl,heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl,tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl,octadecanoyl, nonadecanoyl, icosanoyl, etc.);

lower or higher alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl,t-butoxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl, etc.);

lower or higher alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl,etc.);

lower or higher alkoxysulfonyl (e.g., methoxysulfonyl, ethoxysulfonyl,etc.);

mono(or di or tri)halo(lower)alkylsulfonyl [e.g. fluoromethylsulfonyl,dichloromethylsulfonyl, trifluoromethylsulfonyl, chloromethylsulfonyl,dichloromethylsulfonyl, trichloromethylsulfonyl, 1 or2-fluoroethylsulfonyl, 1 or 2-chloroethylsulfonyl, etc.);

or the like;

Aromatic acyl such as

aroyl (e.g., benzyl, toluoyl, naphthoyl, etc.); ar(lower)alkanoyl [e.g.,phenyl(lower)alkanoyl (e.g., phenylacetyl, phenylpropanoyl,phenylbutanoyl, phenylisobutanoyl, phenylpentanoyl, phenylhexanoyl,etc.), naphthyl(lower)alkanoyl (e.g., naphthylacetyl, naphthylpropanoyl,naphthylbutanoyl, etc.), etc.];

ar(lower)alkenoyl [e.g., phenyl(lower)alkenoyl (e.g., phenylpropenoyl,phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl, phenylhexenoyl,etc.), naphthyl(lower)alkenoyl (e.g., naphthylpropenoyl,naphthylbutenoyl, etc.), etc.];

ar(lower)alkoxycarbonyl [e.g., phenyl(lower)alkoxycarbonyl (e.g.,benzyloxycarbonyl, etc.), etc.];

aryloxycarbonyl (e.g., phenoxycarbonyl, naphthyloxycarbonyl, etc.);

aryloxy(lower)alkanoyl (e.g., phenoxyacetyl, phenoxypropionyl, etc.);

arylglyoxyloyl (e.g., phenylglyoxyloyl, naphthylglyoxyloyl, etc.);

arylsulfonyl (e.g., phenylsulfonyl, p-tolylsulfonyl, etc.); or the like;

Heterocyclic acyl such as

heterocycliccarbonyl; heterocyclic(lower)alkanoyl (e.g.,heterocyclicacetyl, heterocyclicpropanoyl, heterocyclicbutanoyl,heterocyclicpentanoyl, heterocyclichexanoyl, etc.);heterocyclic(lower)alkenoyl (e.g., heterocyclicpropenoyl,heterocyclicbutenoyl, heterocyclicpentenoyl, heterocyclichexenoyl,etc.);

heterocyclicglyoxyloyl; or the like.

in which suitable "heterocyclic moiety" in the terms"heterocycliccarbonyl", "heterocyclic(lower)alkyl",heterocyclic(lower)alkenoyl" and "heterocyclicglyoxyloyl" as mentionedabove means, in more detail, saturated or unsaturated, monocyclic orpolycyclic heterocyclic group containing at least one hetero-atom suchas an oxygen, sulfur, nitrogen atom and the like.

And, especially preferable heterocyclic group may be heterocyclic groupsuch as

unsaturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example,pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl,pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (e.g.,4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.),tetrazolyl (e.g., 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.;

saturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example,pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, etc.;

unsaturated condensed heterocyclic group containing 1 to 4 nitrogenatom(s), for example, indolyl, isoindolyl, indolinyl, indolizinyl,benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, etc.;

unsaturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g.,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.), etc.;

saturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3nitrogen atom(s), for example, oxazolidinyl, morpholinyl, sydnonyl,etc.;

unsaturated condensed heterocyclic group containing 1 to 2 oxygenatom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl,benzoxadiazolyl, etc.;

unsaturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3nitrogen atom(s), for example, triazolyl, isothiazolyl, thiadiazolyl(e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl, etc.), dihydrothiazinyl, etc.;

saturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3nitrogen atom(s), for example, thiazolidinyl, etc.;

unsaturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 to 2 sulfur atom(s) for example,thienyl, dihydrodithiinyl, dihydrodithionyl, etc.;

unsaturated condensed heterocyclic group containing 1 to 2 sulfuratom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl,benzothiadiazolyl, etc.;

unsaturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing an oxygen atom, for example, furyl,etc.;

unsaturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing an oxygen atom and 1 to 2 sulfuratom(s), for example, dihydrooxathiinyl, etc.;

unsaturated condensed heterocyclic group containing 1 to 2 sulfuratom(s), for example, benzothienyl, benzodithiinyl, etc.;

unsaturated condensed heterocyclic group containing an oxygen atom and 1to 2 sulfur atom(s), for example, benzoxathiinyl, etc.; and the like.

The acyl moiety as stated above may have one to ten, same or different,suitable substituent(s) such as lower alkyl as exemplified above; loweralkoxy as exemplified above; lower alkylthio wherein lower alkylmoieties as exemplified above; lower alkylamino wherein lower alkylmoiety is as exemplified above; cyclo(lower)alkyl as exemplified above;cyclo(lower)alkenyl as exemplified above; halogen; amino, protectedamino as exemplified above; hydroxy; protected hydroxy; cyano; nitro;carboxy; protected carboxy; sulfo; sulfamoyl; imino; oxo;amino(lower)alkyl wherein lower alkyl moiety is as exemplified above;carbamoyloxy; hydroxy(lower)alkyl wherein lower alkyl moiety is asexemplified above; diamino(lower)alkylidene (e.g., diaminomethylene,etc.); di(lower)alkylamino wherein lower alkyl moiety is as exemplifiedabove; di(lower)alkylamino(lower)alkyl wherein lower alkyl moiety is asexemplified above; heterocyclic(lower)alkyl wherein heterocyclic moietyand lower alkyl moiety are each as exemplified above, or the like.

Preferable example of amidino-protective group thus defined may be loweralkoxycarbonyl, and the most preferable one may be t-butoxycarbonyl.

Suitable "lower alkanoyl" may include formyl, acetyl, propanoyl,butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl,and the like, in which more preferable example may be C₁ -C₄ alkanoyland the most preferable one may be acetyl.

Suitable "carboxy(lower)alkanoyl" means lower alkanoyl as mentionedabove substituted by carboxy, in which more preferable example may becarboxy(C₁ -C₄)alkanoyl and the most preferable one may becarboxyacetyl.

Suitable "protected carboxy(lower)alkanoyl" means lower alkanoyl asmentioned above substituted by Protected carboxy as mentioned above, inwhich more preferable example may be C₁ -C₄ alkoxycarbonyl(C₁-C₄)alkanoyl and the most preferable one may be ethoxycarbonylacetyl.

Suitable "aroyl" may include C₆ -C₁₀ aroyl such as benzoyl, toluoyl,naphthoyl, and the like, in which the most preferable one may bebenzoyl.

One preferable embodiments of R¹, R², R³, A, X, Y, Z and the line:##STR9## are as follows: R¹ is hydrogen, lower alkylcarbamoyl(loweralkylidene optionally substituted by halogen, lower alkylidene, loweralkyl, ar(lower)alkyl optionally substituted by the group consisting oflower alkyl, lower alkoxy and lower alkylenedioxy,cyclo(lower)alkyl(lower)alkyl, lower alkoxycarbonyl(lower)alkyl,carboxy(lower)alkyl, hydroxy(lower)alkyl, loweralkylcarbamoyl(lower)alkyl optionally substituted by halogen, orarylcarbamoyl(lower)alkyl optionally substituted by the group consistingof lower alkyl, lower alkoxy and lower alkylenedioxy,

R² is hydrogen,

R³ is hydrogen,

A is lower alkylene or carbonyl,

X is ##STR10## Y is lower alkylene, --S-- or --SO₂ --, Z is --S-- or--O--, and

the line: ##STR11## is single bond or double bond.

The processes for the preparation of the object compound (I) of thepresent invention are explained in detail in the following.

(1) Process 1:

The compound (I-a) or a salt thereof can be prepared by converting theester moiety of the compound (II) or a salt thereof to the amidinomoiety.

Suitable salts of the compounds (I-a) and (II) may be the same as thosefor the compound (I).

This reaction can be carried out by a conventional method which canconvert the ester moiety to the amidine moiety such as reacting with acombination of ammonium halide (e.g. ammonium chloride, etc.) andtri(lower)alkylalminum (e.g. trimethylalminum, etc.).

This reaction can be carried out in a conventional solvent which doesnot adversely influence the reaction such as dichloromethane, pyridine,N,N-dimethylformamide, 4-methyl-2-pentanone, tetrahydrofuran, toluene,etc., or a mixture thereof.

The reaction temperature is not critical and the reaction is usuallycarried out under from warming to heating.

(2) Process 2:

The compound (I-c) or a salt thereof can be prepared by reducing thecompound (I-b) or a salt thereof.

Suitable salts of the compounds (I-b) and (I-c) may be the same as thosefor the compound (I).

The reduction method applicable for this removal reaction may include,for example, reduction by using a combination of a metal (e.g. zinc,zinc amalgam, etc.) or a salt of chrome compound (e.g. chromouschloride, chromous acetate, etc.) and an organic or inorganic acid (e.g.acetic acid, propionic acid, hydrochloric acid, sulfuric acid, etc.);and conventional catalytic reduction in the presence of a conventionalmetallic catalyst such as palladium catalysts (e.g. spongy palladium,palladium black, palladium oxide, palladium on carbon, colloidalpalladium, palladium on barium sulfate, palladium on barium carbonate,palladium hydroxide on carbon, etc.), nickel catalysts (e.g. reducednickel, nickel oxide, Raney nickel, etc.), platinum catalysts (e.g.platinum plate, spongy platinum, platinum black, colloidal platinum,platinum oxide, platinum wire, etc.), and the like.

This reaction is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as water, alcohol (e.g.methanol, ethanol, propanoyl, etc.), dioxane, tetrahydrofuran, aceticacid, buffer solution (e.g. phosphate buffer, acetate buffer, etc.), andthe like, or a mixture thereof..

The reaction temperature is not critical and the reaction is usuallycarried out under from cooling to warming.

(3) Process 3:

The compound (I-a) or a salt thereof can be prepared by reacting thecompound (III) or a salt thereof with ammonia or a salt thereof.

Suitable salts of the compound (III) may be the same as those for thecompound (I).

Suitable salts of ammonia may include acid addition salts as mentionedfor the compound (I).

The reaction is usually carried out in a conventional solvent which doesnot adversely influence the reaction such as water, acetone,dichloromethane, alcohol (e.g. methanol, ethanol, etc.),tetrahydrofuran, pyridine, N,N-dimethylformamide, etc., or a mixturethereof.

The reaction temperature is not critical and the reaction is usuallycarried out under from cooling to heating.

(4) Process 4:

The compound (I-e) or a salt thereof can be prepared by subjecting thecompound (I-d) or a salt thereof to a removal reaction of thecarboxy-protective group in R_(c) ¹.

Suitable salts of the compounds (I-d) and (I-e) may be the same as thosefor the compound (I).

The present reaction is usually carried out by a conventional methodsuch as hydrolysis, reduction, and the like.

(i) Hydrolysis:

The hydrolysis is preferably carried out in the presence of a base or anacid. Preferable base may include an alkalimetal hydroxide (e.g. sodiumhydroxide, potassium hydroxide, etc.), an alkaline earth metal hydroxide(e.g. magnesium hydroxide, calcium hydroxide, etc.,), alkali metalhydride (e.g. sodium hydride, potassium hydride, etc.), alkaline earthmetal hydride (e.g. calcium hydride, etc.), alkali metal alkoxide (e.g.sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.), analkali metal carbonate (e.g. sodium carbonate, potassium carbonate,etc.), and alkaline earth metal carbonate (e.g. magnesium carbonate,calcium carbonate, etc.), an alkali metal bicarbonate (e.g. sodiumbicarbonate, potassium bicarbonate, etc.), and the like.

Preferable acid may include an organic acid (e.g. formic acid, aceticacid, propionic acid, trifluoroacetic acid, benzenesulfonic acid,p-toluenesulfonic acid, etc.) and an inorganic acid (e.g. hydrochloricacid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.). Theacidic hydrolysis using trifluoroacetic acid is usually accelerated byaddition of cation trapping agent (e.g. phenol, anisole, etc.).

This reaction is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as water,dichloromethane, alcohol (e.g. methanol, ethanol, etc.),tetrahydrofuran, dioxane, acetone, etc., or a mixture thereof. A liquidbase or acid can be also used as the solvent.

The reaction temperature is not critical and the reaction is usuallycarried out under from cooling to heating.

(ii) Reduction:

The reduction method applicable for this removal reaction may include,for example, reduction by using a combination of a metal (e.g. zinc,zinc amalgam, etc.) or a slat of chrome compound (e.g. chromouschloride, chromous acetate, etc.) and an organic or inorganic acid (e.g.acetic acid, propionic acid, hydrochloric acid, sulfuric acid, etc.);conventional catalytic reduction in the presence of a conventionalmetallic catalyst such as palladium catalysts (e.g. spongy palladium,palladium black, palladium oxide, palladium on carbon, colloidalpalladium, palladium on barium sulfate, palladium on barium carbonate,palladium hydroxide on carbon, etc.), nickel catalysts (e.g. reducednickel, nickel oxide, Raney nickel, etc.), platinum catalysts (e.g.platinum plate, spongy platinum, platinum black, colloidal platinum,platinum oxide, platinum wire, etc.); sodium boro hydride; lithiumaluminum hydride; and the like.

In case that the catalytic reduction is applied, the reaction ispreferable carried out around neutral condition.

This reaction is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as water, alcohol (e.g.methanol, ethanol, propanol, etc.), dioxane, tetrahydrofuran, aceticacid, buffer solution (e.g. phosphate buffer, acetate buffer, etc.), andthe like, or a mixture thereof.

The reaction temperature is not critical and the reaction is usuallycarried out under from cooling to warming.

(5) Process 5:

The compound (I-g) or a salt thereof can be prepared by subjecting thecompound (I-f) or a salt thereof to a removal reaction of thecarboxy-protective group in R_(a) ².

Suitable salts of the compounds (I-f) and (I-g) may be the same as thosefor the compound (I).

The present reaction is usually carried out in substantially the samemanner as that of Process 4, therefore, the reaction conditions (e.g.temperature, solvents, etc.) can be referred to the explanation ofProcess 4.

(6) Process 6:

The compound (I-h) or a salt thereof can be prepared by introducing anamidino-protective group into the compound (I-a) or a salt thereof.

Suitable salts of the compound (I-h) may be the same as those for thecompound (I).

Suitable introducing agent of the amidino-protective group used in thisreaction may be a conventional agent which is capable of introducing theamidino-protective group as mentioned before such as carboxylic acid,carbonic acid, sulfonic acid and their reactive derivative, for example,an acid halide, an acid anhydride, an activated amide, an activatedester, and the like. Preferable example of such reactive derivative mayinclude acid chloride, acid bromide, a mixed acid anhydride with an acidsuch as substituted phosphoric acid (e.g. dialkylphosphoric acid,phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid,halogenated phosphoric acid, etc.), dialkylphosphorous acid, sulfurousacid, thiosulfuric acid, sulfuric acid, alkyl carbonate (e.g. methylcarbonate, ethyl carbonate, propyl carbonate, etc.), aliphaticcarboxylic acid (e.g. pivalic acid, pentanoic acid, isopentanoic acid,2-ethylbutyric acid, trichloroacetic acid, etc.), aromatic carboxylicacid (e.g., benzoic acid, etc.), a symmetrical acid anhydride, anactivated acid amide with a heterocyclic compound containing iminofunction such as imidazole, 4-substituted imidazole, dimethylpyrazole,triazole and tetrazole, an activated ester (e.g. p-nitrophenyl ester,2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester,mesylphenyl ester, phenylazophenyl ester, phenyl thioester,p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester,pyridyl ester, piperidinyl ester, 8-quinolyl thioester, or an ester witha N-hydroxy compound such as N,N-dimethylhydroxylamine,1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide,1-hydroxybenzotriazole, 1-hydroxy-6-chlorobenzotriazole, etc.), and thelike.

This reaction can be carried out In the presence or an organic orinorganic base such as alkali metal (e.g. lithium, sodium, potassium,etc.), alkaline earth metal (e.g. calcium, etc.), alkali metal hydride(e.g. sodium hydride, etc.), alkaline earth metal hydride (e.g. calciumhydride, etc.), alkali metal hydroxide (e.g. sodium hydroxide, potassiumhydroxide, etc.), alkali metal carbonate (e.g. sodium carbonate,potassium carbonate, etc.), alkali metal bicarbonate (e.g. sodiumbicarbonate, potassium bicarbonate, etc.), alkali metal alkoxide (e.g.sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.),alkali metal alkanoic acid (e.g. sodium acetate, etc.), trialkylamine(e.g. triethylamine, etc.), pyridine compound (e.g. pyridine, lutidine,picoline, 4-dimethylaminopyridine, etc.), quinoline, and the like.

In case that the introducing agent is used in a free form or its salt inthis reaction, the reaction is preferably carried out in the presence ofa condensing agent such as a carbodiimide compound [e.g.N,N'-dicyclohexylcarbodiimide,N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide,N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide,N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide, etc.], a keteniminecompound (e.g. N,N'-carbonylbis(2-methylimidazole),pentamethyleneketene-N-cyclohexylimine,diphenylketene-N-cyclohexylimine, etc.); an olefinic or acetylenic ethercompounds (e.g. ethoxyacetylene, β-chlorovinylethyl ether), a sulfonicacid ester of N-hydroxybenzotriazole derivative [e.g.1-(4-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole, etc.], acombination of trialkylphosphite or triphenylphosphine and carbontetrachloride, disulfide or diazenedicarboxylate (e.g. diethyldiazenedicarboxylate, etc.), a phosphorus compound (e.g. ethylpolyphosphate, isopropyl polyphosphate, phosphoryl chloride, phosphorustrichloride, etc.), thionyl chloride, oxalyl chloride,N-ethylbenzisoxazolium salt, N-ethyl-5-phenylisoxazolium-3-sulfonate, areagent (referred to a so-called "Vilsmeier reagent") formed by thereaction of an amide compound such as N,N-di(lower)alkylformamide (e.g.dimethylformamide, etc.), N-methylformamide or the like with a halogencompound such as thionyl chloride, phosphoryl chloride, phosgene or thelike.

The reaction is usually carried out in a conventional solvent which doesnot adversely influence the reaction such as water, acetone,dichloromethane, alcohol (e.g. methanol, ethanol, etc.),tetrahydrofuran, pyridine, N,N-dimethylformamide, etc., or a mixturethereof.

The reaction temperature is not critical and the reaction is usuallycarried out under from cooling to heating.

(7) Process 7:

The compound (I-i) or a salt thereof can be prepared by reacting thecompound (I-g) or its reactive derivative at the carboxy group, withN-(lower)alkyl-N-(lower)alkoxyamine or a salt thereof.

Suitable salts of the compound (I-i) may be the same as those for thecompound (I).

Suitable salts of N-(lower)alkyl-N-(lower)alkoxyamine may be the sameacid addition salts as mentioned for the compound (I).

Suitable reactive derivative at the carboxy group of the compound (I-g)may include an acid halide, an acid anhydride, an activated amide, anactivated ester, and the like. Suitable examples of the reactivederivatives may be an acid chloride; an acid azide; a mixed acidanhydride with acid such as substituted phosphoric acid [e.g.dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid,dibenzylphosphoric acid, halogenated phosphoric acid, etc.],dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuricacid, sulfonic acid [e.g. methanesulfonic acid, etc.], aliphaticcarboxylic acid [e.g. acetic acid, propionic acid, butyric acid,isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid,2-ethylbutyric acid, trichloroacetic acid, etc.] or aromatic carboxylicacid [e.g. benzoic acid, etc.]; a symmetrical acid anhydride; anactivated amide with imidazole, 4-substituted imidazole,dimethylpyrazole, triazole or tetrazole; or an activated ester [e.g.cyanomethyl ester, methoxymethyl ester, dimethyliminiomethyl ##STR12##ester, vinyl ester, propargyl ester, p-nitrophenyl ester,2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester,mesylphenyl ester, phenylazophenyl ester, phenyl thioester,p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester,pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester,etc.], or an ester with a N-hydroxy compound [e.g.N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone,N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole,etc.], and the like. These reactive derivatives can optionally beselected from them according to the kind of the compound (I-g) to beused.

The reaction is usually carried out in a conventional solvent such aswater, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane,acetonitrile, chloroform, methylene chloride, ethylene chloride,tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or anyother organic solvent which does not adversely influence the reaction.These conventional solvent may also be used in a mixture with water.

In this reaction, when the compound (II) is used in a free acid form orits salt form, the reaction is preferably carried out in the presence ofa conventional condensing agent such as N,N'-dicyclohexylcarbodiimide;N-cyclohexyl-N'-morpholinoethyl carbodiimide;N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide;N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide;N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide;N,N'-carbonylbis(2-methylimidazole);pentamethyleneketene-N-cyclohexylimine;diphenylketene-N-cyclohexylimine; ethoxyacetylene;1-alkoxy-1-chloroethylene; trialkyl phosphite;O-benzotriazol-1-yl-N,N,N',N'-tetramethylurenium hexafluorophosphate;ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride(phosphoryl chloride); phosphorus trichloride; diphenyl phosphorylazide;thionyl chloride; oxalyl chloride; lower alkyl haloformate [e.g. ethylchloroformate, isopropyl chloroformate, etc.]; triphenylphosphine;2-ethyl-7-hydroxybenzisoxazolium salt;2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intramolecular salt;N-hydroxybenzotriazole;1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; so-calledVilsmeier reagent prepared by the reaction of N,N-dimethylformamide withthionyl chloride, phosgene, trichloromethyl chloroformate, phosphorusoxychloride, etc.; or the like.

The reaction may also be carried out in the presence of an inorganic ororganic base such as an alkali metal bicarbonate, tri(lower)alkylamine(e.g. triethylamine, etc.), pyridine, N-(lower)alkylmorpholine,N,N-di-(lower)alkylbenzylamine, or the like.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to warming.

(8) Process 8:

The compound (I-a) or a salt thereof can be prepared by subjecting thecompound (I-h) or a salt thereof to a removal reaction of theamidino-protective group of R_(a) ³.

The present reaction is usually carried out in substantially the samemanner as that of Process 4, therefore, the reaction conditions (e.g.temperature, solvents, etc.) can be referred to the explanation ofProcess 4.

(9) Process 9:

The compound (I-k) or a salt thereof can be prepared by reducing thecompound (I-j) or a salt thereof.

Suitable salts of the compounds (I-j) and (I-k) may be the same as thosefor the compound (I).

The present reaction is usually carried out in substantially the samereduction reaction as that of Process 4, therefore, the reactionconditions (e.g. temperature, solvents, etc.) can be referred to theexplanation of Process 4.

Urokinase Inhibiting Effect

Now in order to show the utility of the object compound (I) andpharmaceutically acceptable salts, the test datum on urokinaseinhibiting effect of the representative compound of the compound (I) ofthis invention is shown in the following.

Test Compound:

Compound A [The product of Example 2-1)]

Test Method:

Test Compound was incubated at desired concentrations with 25International Units (IU)/ml human high molecular weight urokinase(Fujisawa Pharmaceutical Co., Ltd.) and urokinase substrate (S-2288,H-D-Isoleucyl-L-prolyl-L-arginine-n-nitroaniline dihydrochloride;Chromagenix, Sweden; Japan distributors Daiichikagakuyakuhin Co., Ltd.)in a 100 μl final volume of 50 mM Tris, 100 mM NaCl, 1 mM Na₂ EDTA,0.01% (v/v) polyoxyethylenesorbitan monooleate (Tween 80), pH 7.5(Buffer Z). Incubations were carried out at 37° C. for 30 minutes. Colorwas quantitated by measuring absorbance at 405 nm (A₄₀₅) using EL312Automated Microplate Reader.

Test Result:

    ______________________________________                                        Test Compound   IC.sub.50 (μM)                                             ______________________________________                                        Compound A      0.47                                                          ______________________________________                                    

For therapeutic administration, the object compound (I) and thepharmaceutically acceptable salts thereof of the present invention areused in the form or conventional pharmaceutical preparation whichcontains said compound, as an active ingredient, in admixture withpharmaceutically acceptable carriers such as an organic or inorganicsolid or liquid excipient which is suitable for oral, parenteral andexternal administration. The pharmaceutical preparations may be in solidform such as tablet, granule, powder, capsule, or liquid form such assolution, suspension, syrup, emulsion, lemonade, and the like.

If needed, there may be included in the above preparations auxiliarysubstances, stabilizing agents, wetting agents and other commonly usedadditives such as lactose, stearic acid, magnesium stearate, terra alba,sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, oliveoil, cacao butter, ethylene glycol, tartaric acid, citric acid, fumaricacid, and the like.

While the dosage of the compound (I) may vary from and also depend uponthe age, condition of the patient, a kind of diseases, a kind of thecompound (I) to be applied, etc. In general, amount between about 0.001mg and about 300 mg, preferably about 0.1 mg to about 50 mg per day maybe administered to a patient. An average single dose of about 0.001 mg,0.01 mg, 0.03 mg, 0.1 mg, 0.3 mg, 0.6 mg, 1.0 mg, 3.0 mg, 10.0 mg, 50.0mg, 100.0 mg of the object compound (I) of the present invention may beused.

The following Preparations and Examples are given for the purpose ofillustrating this invention in more detail.

Preparation 1-1)

Diethyl ethoxycarbonylmethylphosphonate (8.47 ml) was dropwise added toa mixture of sodium hydride (60), 1.71 g) and tetrahydrofuran (THF) (50ml) at room temperature (r.t.) under nitrogen atmosphere, and themixture was stirred under the same condition for 30 minutes. To thereaction mixture was added 4-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene(5.00 g) in a portion, and the whole mixture was stirred at r.t. for 3hours. The reaction mixture was poured into a mixture of water and ethylacetate (AcOEt). The separated organic layer was washed with water andbrine, and dried over magnesium sulfate (MgSO₄), and dried in vacuo toprecipitate. The resulting precipitate was washed with isopropyl ether(iPE) to give4-ethoxycarbonylmethylidene-4,5,6,7-tetrahydrobenzo[b]thiophene (5.91g).

IR (Nujol): 1700, 1605 cm⁻¹ ; MASS (z/e): 223 (M+H)⁺ ; NMR (DMSO-d₆, δ):1.31 (3H, t, J=7.1 Hz), 2.01 (24, m), 2.89 (2H, t, J=7.1 Hz), 3.15 (2H,m), 4.19 (2H, t, J=7.1 Hz), 5.67 and 6.11 (1H, each s), 7.06 (1H, d,J=5.4 Hz), 7.20 (1H, d, J=5.4 Hz).

Preparation 1-2)

The following compound was obtained according to a similar manner tothat of Preparation 3-3).

4-Carboxymethylidene-4,5,6,7-tetrahydrobenzo[b]thiophene

NMR (DMSO-d₆, δ): 1.84 (2H, tt, J=5.7, 6.1 Hz), 2.85 (2H, t, J=6.1 Hz),3.03 (2H, t, J=5.7 Hz), 6.14 (1H, s), 7.33 (1H, d, J=5.4 Hz), 7.39 (1H,d, J=5.4 Hz), 11.99 (1H, br s).

Preparation 1-3)

To a mixture of 4-carboxymethylidene-4,5,6,7-tetrahydrobenzo[b]thiophene(0.50 g), n-butylamine (0.28 ml), 1-hydroxybenzotriazole (0.43 g) anddimethylformamide (DMF) (5 ml) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.54 g).The reaction mixture was stirred at r.t. for 5 hours and poured into amixture of AcOEt and a saturated aqueous solution of sodium hydrogencarbonate (NaHCO₃). The separated organic layer was washed with waterand brine, and dried over MgSO&, and evaporated to give4-(N-butylcarbamoyl)methylidene-4,5,6,7-tetrahydrobenzo[b]thiophene(0.60 g).

MASS (z/e): 250 (M+H)⁺ ; NMR (DMSO-d₆, δ): 0.88 (3H, t, J=7.2 Hz),1.2-1.4 (4H, m), 1.7-1.9 (2H, m), 2.82 (2H, d, J=6.0 Hz), 3.0-3.2 (4H,m), 6.21 (1H, s), 7.18 (1H, d, J=5.4 Hz), 7.33 (1H, d, J=5.4 Hz), 7.84(1H, br s).

Preparation 1-4)

To a mixture of4-(N-butylcarbamoyl)methylidene-4,5,6,7-tetrahydrobenzo[b]thiophene(0.49 g) and THF (8 ml) was dropwise added 1.64 M n-butyl lithium(n-BuLi) in n-hexane (2.88 ml) at -70˜-60° C. under nitrogen atmosphereand the mixture was stirred under the same condition for 2.5 hours. Thereaction mixture was poured into a mixture of dry ice and diethyl ether(Et₂ O). To the mixture were added Et₂ O and water. The separatedaqueous layer was washed with Et₂ O, and acidified by 6 N hydrochloricacid (HCl) and was extracted with AcOEt. The organic layer was washedwith water and brine, and dried over MgSO₄, and evaporated in vacuo togive4-(N-butylcarbamoyl)methylidene-4,5,6,7-tetrahydrobenzo[b]-thiophene-2-carboxylicacid (0.38 g).

This product was used in the following reaction without isolation.

Preparation 1-5)

A mixture of4-(N-butylcarbamoyl)methylidene-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylicacid (0.57 g), conc. sulfuric acid (H₂ SO₄) (3 ml), and methanol (MeOH)(15 ml) was stirred at reflux for 1.5 hours. The reaction mixture waspoured into a mixture of AcOEt and water. The organic layer was washedwith saturated aqueous solution of NaHCO₃, water and brine, and driedover MgSO₄, and evaporated in vacuo. After evaporation, the resultingoil was purified by chromatography on silica gel (AcOEt-n-hexane as aneluent). The fractions including the object compound were collected andevaporated to give4-(N-butylcarbamoyl)methylidene-2-methoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophene(115.3 mg).

NMR (DMSO-d₆, δ): 0.89 (3H, t, J=6.9 Hz), 1.2-1.6 (4H, m), 1.7-2.0 (2H,m), 2.78 (2H, t, J=6.0 Hz), 3.0-3.2 (4H, m), 3.82 (3H, s), 6.39 (1, s),7.78 (1H, t, J=5.5 Hz), 7.89 (1H, s).

Preparation 2-1)

The following compound was obtained according to a similar manner tothat of Preparation 4-1).

4-n-Butylidene-4,5,6,7-tetrahydrobenzo[b]thiophene

MASS (z/e): 193 (M+H)⁺ ; NMR (CDCl₃, δ) 0.9-1.0 (3H, m), 1.3-1.6 (2H,m), 1.7-2.9 (8H, m), 5.5 and 5.8 (1H, t, J=7.4 Hz), 6.9-7.2 (2H, m).

Preparation 2-2)

The following compound was obtained according to a similar manner tothat of Preparation 1-4).

4-n-Butylidene-2-carboxy-4,5,6,7-tetrahydrobenzo[b]-thiophene

MASS (z/e): 237 (M+H)⁺ ; NMR (CDCl₃, δ): 0.85 (3H, t, J=6.5 Hz), 0.9-2.0(8H, m), 2.6-3.0 (2H, m), 4.83 (1H, s), 7.61 (1H, s), 12.83 (1H, br s).

Preparation 2-3)

The following compound was obtained according to a similar manner tothat of Preparation 4-3).

4-n-Butylidene-2-methoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophene

IR (Neat): 2954, 2866, 1713, 1543 cm⁻¹ ; NMR (DMSO-d₆, δ): 0.8-1.0 (3H,m), 1.2-3.0 (10H, m), 3.80 (3H, s), 5.62 and 5.97 (1H, each t, J=7.2Hz), 7.64 and 7.93 (1H, each s).

Preparation 3-1)

The following compound was obtained according to a similar manner tothat of Preparation 1-1).

Ethyl 5-(2-thienyl)-2,4-pentadienoate

NMR (CDCl₃, δ): 1.30 (3H, t, J=7.1 Hz), 4.23 (2H, q, J=7.1 Hz), 5.94(1H, d, J=15.2 Hz), 6.66 (1H, dd, J=15.2, 11.1 Hz), 7.0-7.6 (5H, m)

Preparation 3-2)

A mixture of ethyl 5-(2-thienyl)-2,4-pentdienoate (20.20 g), 10%palladium hydroxide (Pd(OH)₂) (2.04 g), THF (200 ml), MeOH (100 ml) and1 N HCl (10 ml) was stirred at r.t. under nitrogen atmosphere for 3.5hours. After removal of insoluble solids, the filtrate was evaporated invacuo, and the residue was dissolved with a mixture of AcOEt and water.The organic layer was washed with saturated aqueous solution of NaHCO₃,water and brine, and dried over MgSO₄, and evaporated in vacuo to giveethyl 5-(2-thienyl)pentanoate (15.70 g).

MASS (z/e): 211 (M-H)⁺ ; NMR (DMSO-d₆, δ): 1.25 (3H, m), 1.4-3.0 (8H,m), 4.2 (2H, m), 6.8-7.2 (3H, m).

Preparation 3-3)

A mixture of ethyl 5-(2-thienyl)pentanoate (15.40 g), sodium hydroxide(NaOH) (2.90 g), water (H₂ O) (18 ml), and tetrahydrofuran (THF) (100ml) was stirred at reflux for 2.5 hours. The reaction mixture was pouredinto a mixture of water and diethyl ether (Et₂ O). The aqueous layer wasseparated, and acidified with 6 N hydrochloric acid (HCl), and extractedwith ethyl acetate (AcOEt). The organic layer was washed with water andbrine, and dried over magnesium sulfate (MgSO₄), and evaporated to give5-(2-thienyl)pentanoic acid (12.07 g) as an oil.

NMR (CDCl₃, δ): 1.6-3.0 (8H, m), 6.9-7.2 (3H, m).

Preparation 3-4)

To a mixture of 5-(2-thienyl)pentanoic acid (5.04 g) and toluene (50 ml)was dropwise added trifluoroacetic anhydride (6.95 ml) over 1 minutewith ice-water cooling. The reaction mixture was stirred at roomtemperature (r.t.) overnight, and was poured into a mixture of asaturated aqueous solution of sodium hydrogen carbonate (NaHCO₃) andAcOEt. The organic layer was washed with water and brine, and dried overMgSO₄, and evaporated. The resulting oil was purified by chromatographyon silica gel (SiO₂) (20% AcOEt in n-hexane as eluent). The fractionsincluding the object compound were combined and evaporated to give4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene (1.57 g) as an oil.

MASS (z/e): 167 (M+H)⁺ ; NMR (CDCl₃, δ): 1.90 (2H, m), 2.70 (2H, m),3.10 (2H, m), 6.98 (1H, d, J=5.3 Hz), 7.41 (1H, d, J=5.3 Hz).

Preparation 3-5)

A mixture of sodium hydride (NaH) (60% in Nujol, 0.69 g) and dimethylsulfoxide (DMSO) (9 ml) was stirred at 70° C. for 2 hours. Abatercooling to r.t., THF (6 ml) and n-butyl-triphenylphosphonium bromide(7.26 g) were added thereto. The reaction mixture was stirred at r.t.for 1 hour, and then 4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene(1.44 g) was added. The mixture was stirred at r.t. overnight and pouredinto a mixture of a saturated aqueous solution of ammonium chloride (NH₄Cl) and AcOEt. The separated organic layer was washed with water andbrine, and dried over MgSO₄, and evaporated. The resulting oil waspurified by chromatography on SiO₂ (1% AcOEt in n-hexane as eluent). Thefractions containing the object compound were combined and evaporated togive 4-n-butylidene-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene (1.15g) as an oil.

MASS (z/e): 251 (M+H)⁺ ; NMR(CHCl₃, δ): 0.7-3.0 (15H, m), 5.44 and 5.59(1H, each t, J=7.4 Hz each), 6.8-7.0 (2H, m).

Preparation 3-6)

The following compound was obtained according to a similar manner tothat of Preparation 4-2).

4-n-Butylidene-5,6,7,8-tetrahydro-4H-cyclohepta[b]-thiophene-2-carboxylicacid MASS (z/e): 251 (M+H)⁺ ;

NMR (DMSO-d₆, δ): 0.8-3.0 (15H, m), 5.51 and 5.62 (1H, each t, J=7.3 and7.4 Hz), 7.59 and 7.68 (1H, each s).

Preparation 3-7)

N-Methylmorpholine (0.69 ml) was added to a mixture of4-n-butylidene-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-2-carboxylicacid (1.05 g) and THF (10 ml) at -15˜-20° C. under nitrogen atmosphere,and isobutyl chloroformate (0.82 ml) was added thereto over 2 minutes.The mixture was stirred under the same condition for 30 minutes, andconc. ammonia (c.NH₃) was added thereto. The mixture was stirred at r.t.for 2 hours. The reaction mixture was poured into a mixture of water andAcOEt to precipitate. The precipitate was collected by filtration,washed with water and Et₂ O, and dried in vacuo to give4-n-butylidene-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-2-carboxamide(0.59 g).

NMR (CDCl₃, δ): 0.8-3.0 (15H, m), 5.48 and 5.59 (1H, each t, J=7.3 and7.3 Hz), 5.77 (2H, br s), 7.27 and 7.35 (1H, each s).

Preparation 3-8)

Phosphorus oxychloride (0.30 ml) was added to a mixture of4-n-butylidene-5,6,7,8-tetrahydro-4H-cyclohepta[b]-thiophene-2-carboxamide(0.55 g, and dimethylformamide (DMF) (6 ml) with ice-water cooling undernitrogen atmosphere, and the mixture was stirred under the samecondition for 1 hour. The reaction mixture was poured into an ice-cooledmixture of an aqueous solution of NaHCO₃ and AcOEt to precipitate. Theprecipitate was collected by filtration, washed with water, and dried invacuo to give4-n-butylidene-5,6,7,8-tetrahydro-2-cyano-4H-cyclohepta[b]thiophene(0.42 g), which was immediately used in the next reaction.

IR (KBr): 2929, 2863, 2213, 1710, 1679, 1616 cm⁻¹.

Preparation 3-9)

The following compound was obtained according to a similar tanner tothat of Preparation 5-2).

4-n-Butylidene-2-(1-ethoxy-1-iminomethyl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene,which was used in the following reaction without isolation.

Preparation 4-1)

To a mixture of 4-oxo-4,5,6,7-tetrahydrobenzo[b]furan (20.06 g) and THF(200 ml) was added dropwise 2M n-butylmagnesium bromide with ice-watercooling over 15 minutes. The mixture was stirred at r.t. overnight. Thereaction mixture was poured into a mixture of a saturated aqueoussolution of NH₄ Cl and AcOEt. The separated organic layer was washedwith water and brine, and dried over MgSO₄, and evaporated. Theresulting oil was purified by chromatography on SiO₂ (CHCl₃ as eluent)to give 4-n-butylidene-4,5,6,7-tetrahydrobenzo[b]furan as a yellow oil(12.06 g).

NMR (CDCl₃, δ): 0.85 (3H, m), 1.2-2.8 (10H, m), 5.28 and 5.51 (1H, t,J=7.4 Hz), 6.2-6.4 (11, m), 7.2-7.3 (1H, m).

Preparation 4-2)

To a mixture of 1.66 N n-butyl lithium (nBuLi) (328 m in n-hexanesolution) and Et₂ O (100 ml) was added a mixture of4-n-butylidene-4,5,6,7-tetrahydrobenzo[b]furan (9.60 g) and Et₂ O (50ml) dropwise over 5 minutes while maintaining -30˜-20° C. by dryice--carbon tetrachloride (CCl₄) cooling. The reaction mixture wasstirred at r.t. for 1 hour, and was bubbled by carbon dioxide (CO₂) gasfor 1 hour. The whole mixture was stirred at r.t. overnight and pouredinto a mixture of water and Et₂ O. The separated aqueous layer wasadjusted to pH 1.4 with 10% HCl, and extracted by AcOEt. The organiclayer was washed with brine, dried over MgSO₄, and evaporated to give4-n-butylidene-4,5,6,7-tetrahydrobenzo[b]-furan-2-carboxylic acid (3.91g) as a reddish oil, which was used in the next reaction without furtherpurification.

Preparation 4-3)

A mixture of4-n-butylidene-4,5,6,7-tetrahydrobenzo[b]-furan-2-carboxylic acid (3.91g) obtained in Preparation 4-2), conc. sulfuric acid (H₂ SO₄) (10 ml),and methanol (MeOH) (100 ml) was stirred at reflux for 1.5 hours. Afterbeing concentrated in vacuo to remove MeOH, the resulting mixture waspoured into a mixture of AcOEt and water. The separated organic layerwas washed with water and brine, dried over MgSO₄, and evaporated. Theresulting oil was purified by chromatography on SiO₂ (7% AcOEt inn-hexane as eluent) to give4-n-butylidene-2-methoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]furan (1.72g) as an oil.

MASS (z/e): 235 (M+H)⁺ ; NMR (CDCl₃, δ): 0.93 (3H, t, J=7.4 Hz), 1.40(2H, m), 1.85 (2H, m), 2.15 (2H, q, J=7.4 Hz), 2.40 (2H, m), 2.74 (2H,t, J=7.4 Hz), 3.88 and 3.90 (3H, each s), 5.25 and 5.61 (1H, each t,J=7.5 Hz), 7.26 (1H, s).

Preparation 5-1)

To a solution of1-n-butyl-6-cyano-2-oxo-2,3-dihydro-1-thieno[2,3-b][1,4]thiazine (0.43g) in chloroform (15 ml) was added m-chloroperbenzoic acid (0.88 g)under ice cooling. After stirring for 22 hours at room temperature, thereaction mixture was poured into a mixture of ethyl acetate andsaturated aqueous sodium thiosulfate. The organic layer was successivelywashed with 20% aqueous potassium carbonate, water and brine and driedover magnesium sulfate. The solvent was evaporated in vacuo and theresidue was purified by column chromatography on silica gel eluting withchloroform. The fractions containing the object compound were collectedand evaporated in vacuo to give1-n-butyl-6-cyano-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine1,1-dioxide (0.32 g).

IR (Nujol): 2220, 1685, 1540 cm⁻¹ ; NMR (DMSO-d₆, δ): 0.88 (3H, t, J=7.2Hz), 1.1-1.6 (4H, m), 3.9-4.1 (2H, m), 5.04 (2H, s), 8.38 (1H, s).

Preparation 5-2)

A mixture of1-n-butyl-6-cyano-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine1,1-dioxide (0.30 g) and ethanol (EtOH) (15 ml) was bubbled withhydrogen chloride under ice-water cooling for 15 minutes. After beingsaturated with hydrogen chloride, the mixture was stood at r.t. for 3hours. The reaction mixture was evaporated to give precipitate. Theresulting precipitate was washed with IPE to give1-n-butyl-2-oxo-2,3-dihydro-6-(1-ethoxy-1-iminomethyl)-1H-thieno-[2,3-b][1,4]thiazinehydrochloride (0.32 g).

IR (Nujol): 1685, 1630 cm⁻¹ ; (+) APCI MASS: 331 (M+H)⁺ ; NMR (DMSO-d₆,δ): 0.8-1.0 (3H, m), 1.2-1.7 (7H, m), 3.8-4.1 (2H, m), 4.53 (2H, q,J=7.0 Hz), 5.04 (2H, s), 8.80 (1H, s).

Preparation 6-1)

The following compound was obtained according to a similar manner tothat of Preparation 15-6).

1-n-Butyl-2,3-dihydro-6-methoxycarbonyl-2-oxo-1H-thieno[2,3-b][1,4]thiazine

NMR (DMSO-d₆, δ): 0.87 (3H, t, J=7.2 Hz), 1.2-1.6 (4H, m), 3.69 (2H, s),3.83 (3H, s), 3.9-4.0 (2H, m), 7.78 (1H, s).

Preparation 6-2)

To a solution of1-n-butyl-2,3-dihydro-6-methoxycarbonyl-2-oxo-1H-thieno[2,3-b][1,4]thiazine(31.9 g) in tetrahydrofuran (300 ml) was added dropwiseboran-tetrahydrofuran complex (1.0 M solution in tetrahydrofuran) (294ml). After stirring for 3 hours at room temperature, the solvent wasevaporated in vacuo and the residue was poured into water. The solutionwas adjusted to pH 8 with 20% aqueous potassium carbonate and extractedwith ethyl acetate. The extract was washed with water and brine, anddried over magnesium sulfate. The solvent was evaporated in vacuo andthe residue was purified by column chromatography on silica gel elutingwith toluene. The fractions containing the object compound werecollected and evaporated in vacuo to give1-n-butyl-2,3-dihydro-6-methoxycarbonyl-1H-thieno-[2,3-b][1,4]thiazine(30.85 g).

IR (Film): 2950, 2850, 1700, 1550 cm⁻¹ ; (+) APCI MASS: 272 (M+H)⁺ ; NMR(DMSO-d₆, δ): 0. 90 (3H, t, J=7.1 Hz), 1.2-1.6 (4H, m), 3.1-3.3 (4H, m),3.4-3.5 (2H, m,) 3.77 (3H, s) 7.37 (1H, s).

Preparation 7-1)

The following compound was obtained according to a similar manner tothat of Preparation 15-6).

1-Benzyl-2,3-dihydro-6-methoxycarbonyl-2-oxo-1H-thieno-[2,3-b][1,4]thiazine

IR (Nujol): 1720, 1660 cm⁻¹ ; NMR (DMSO-d₆, δ): 3.77 (3H, s), 3.85 (2H,s), 5.18 (2H, s), 7.2-7.4 (5H, m), 7.65 (1H, s).

Preparation 7-2)

The following compound was obtained according to a similar manner tothat of Preparation 6-2).

1-Benzyl-2,3-dihydro-6-methoxycarbonyl-1H-thieno[2,3-b][1, 4]thiazine

IR (Nujol): 1690, 1540 cm⁻¹ ; (+) APCI MASS: 306 (M+H)⁺ ; NMR (DMSO-d₆,δ): 3.1-3.2 (2H, m), 3.4-3.6 (2H, m), 3.74 (3H, s), 4.47 (2H, s),7.2-7.5 (6H, m).

Preparation 8-1)

The following compound was obtained according to a similar manner tothat of Preparation 15-6) by using 3,4-dimethoxyphenethylp-toluenesulfonate.

2,3-Dihydro-6-methoxycarbonyl-1-(3,4-dimethoxyphenethyl)-2-oxo-1H-thieno[2,3-b][1,4]thiazine

(+) APCI MASS: 394 (M+H)⁺ ; NMR (DMSO-d₆, δ): 2.6-2.8 (2H, m), 3.6-3.7(8H, m), 3.81 (3H, s), 4.0-4.2 (2H, m), 6.6-6.9 (3H, m), 7.61 (1H, s).

Preparation 8-2)

The following compound was obtained according to a similar manner tothat of Preparation 1 5-6) by using cyclohexylmethyl bromide.

1-Cyclohexylmethyl-2,3-dihydro-6-methoxycarbonyl-2-oxo-1H-thieno[2,3-b][1,4]thiazine

(IR Nujol): 1710, 1655, 1550 cm⁻¹ ; (+) APCI MASS: 326 (M+H)⁺ ; NMR(DMSO-d₆, δ): 0.8-1.2 (5H, m), 1.4-1.8 (6H, m), 3.69 (2H, s), 3.7-3.9(5H, m), 7.83 (1, s).

Preparation 8-3)

The following compound was obtained according to a similar manner tothat of Preparation 15-6) by using phenethyl bromide.

2,3-Dihydro-6-methoxycarbonyl-2-oxo-1-phenethyl-1H-thieno[2,3-b][1,4]thiazine

(+) APCI MASS: 334 (M+H)⁺ ; NMR (DMSO-d₆, δ): 2.7-2.9 (2H, m), 3.67 (2H,s), 3.82 (3H, s), 4.0-4.2 (2H, m), 7.1-7.3 (5H, m), 7.68 (1H, s).

Preparation 8-4)

The following compound was obtained according to a similar manner tothat of Preparation 15-6) by using 3,4-methylenedioxyphenethylp-toluenesulfonate.

2,3-Dihydro-6-methoxycarbonyl-1-(3,4d-methylenedioxyphenethyl)-2-oxo-1H-thieno[2,3-b][1,4]thiazine

(+) APCI MASS: 378 (M+H)⁺ ; NMR (DMSO-d₆, δ): 2.6-2.8 (2H, m), 3.67 (2H,s), 3.82 (3H, s), 4.0-4.2 (2H, m), 6.5-6.6 (1H, m), 6.75 (1H, d, J=7.9Hz), 6.79 (1H, d, J=1.4 Hz), 7.64 (1H, s).

Preparation 8-5)

The Following compound was obtained according to a similar manner tothat of Preparation 15-6) by using benzyl bromide.

1-Benzyl-6-ethoxycarbonyl-2,3-dihydro-2-oxo-1H-thieno[2,3-b][1,4]thiazineIR (Nujol): 1705, 1645, 1550 cm⁻¹ ;

(+) APCI MASS: 334 (M+H)⁺ ; NMR (DMSO-d₆, δ): 1.24 (3H, t, J=7.1 Hz),3.85 (2H, s), 4.23 (2H, q, J=7.1 Hz), 5.18 (2H, s), 7.1-7.4 (5H, m),7.65 (1H, s).

The following compounds were obtained according to a similar manner tothat of Preparation 3-3).

Preparation 9-1)

6-Carboxy-2,3-dihydro-1-(3,4-dimethoxyphenethyl)-2-oxo-1H-thieno[2,3-b][1,4]thiazine

IR (Nujol): 1690, 1615, 1515 cm⁻¹ ; (+) APCI MASS: 380 (M+H)⁺ ; NMR(DMSO-d₆, δ): 2.6-2.8 (2H, m), 3.6-3.8 (8H, m), 4.0-4.2 (2H, m), 6.6-6.9(3H, m), 7.56 (1H, s).

Preparation 9-2)

6-Carboxy-1-cyclohexylmethyl-2,3-dihydro-2-oxo-1H-thieno[2,3-b][1,4]thiazin

IR (Nujol): 1690, 1605, 1545 cm⁻¹ ; (+) APCI MASS: 312 (M+H)⁺ ; NMR(DMSO-d₆, δ): 0.8-1.3 (5H, m), 1.4-1.8 (6H, m), 3.67 (2H, s), 3.79 (2H,d, J=6.9 Hz), 7.73 (1H, s).

Preparation 9-3)6-Carboxy-2,3-dihydro-2-oxo-1-phenethyl-1H-thieno-[2,3-b][1,4]thiazine

IR (Nujol): 1690, 1615 cm⁻¹ ; (+) APCI MASS: 320 (M+H)⁺ ; NMR (DMSO-d₆,δ): 2.7-2.9 (2H, m), 3.66 (2H, s), 4.0-4.2 (2H, m), 7.1-7.3 (5H, m),7.61 (1H, s).

Preparation 9-4)

6-Carboxy-2,3-dihydro-1-(3,4-methylenedioxyphenethyl)-2-oxo-1H-thieno[2,3-b][1,4]thiazine

IR (Nujol): 1685, 1605 cm⁻¹ ; (+) APCI MASS: 364 (M+H)⁺ ; NMR (DMSO-d₆,δ): 2.6-2.8 (2H, m), 3.66 (2H, s), 4.0-4.2 (2H, m), 5.93 (2H, s), 6.59(1H, dd, J=1.5, 7.9 Hz), 6.75 (1H, d, J=7.9 Hz), 6.79 (1H, d, J=1.5 Hz),7.56 (1H, s), 13.27 (1H, br s).

Preparation 9-5)

1-Benzyl-6-carboxy-2,3-dihydro-2-oxo-1H-thieno[2,3-b][1,4]thiazine

IR (Nujol): 1690, 1615 cm⁻¹ ; (+) APCI MASS: 306 (M+H)⁺ ; NMR (DMSO-d₆,δ): 3.84 (2H, s), 5.16 (2H, s), 7.2-7.4 (5H, m), 7.54 (1H, s), 13.27(1H, br s).

Preparation 10-1)

The following compound was obtained according to a similar manner tothat of Preparation 3-7).

6-Carbamoyl-2,3-dihydro-1-(3,4-dimethoxyphenethyl)-2-oxo-1H-thieno[2,3-b][1,4]thiazine

IR (Nujol): 1635, 1510 cm⁻¹ ; (+) APCI MASS: 379 (M+H)⁺ ; NMR (DMSO-d₆,δ): 2.7-2.9 (2H, m), 3.6-3.8 (8H, m), 3.9-4.1 (2H, m), 6.7-6.9 (3H, m),7.51 (1H, br s), 7.78 (1H, s), 7.97 (1H, br s).

The following compounds were obtained according to a similar manner tothat of Preparation 10-1).

Preparation 10-2)

6-Carbamoyl-1-cyclohexylmethyl-2,3-dihydro-2-oxo-1H-thieno[2,3-b][1,4]thiazine

IR (Nujol): 3300, 3170, 1655, 1600 cm⁻¹ ; (+) APCI MASS: 311 (M+H)⁺ ;NMR (DMSO-d₆, δ): 0.8-1.3 (5H, m), 1.5-1.8 (6H, m), 3.6-3.8 (4H, m),7.52 (1H, br s), 7.77 (1H, s), 8.00 (1H, br s).

Preparation 10-3)

6-Carbamoyl-2,3-dihydro-2-oxo-1-phenethyl-1H-thieno-[2,3-b][1,4]thiazine

IR (Nujol): 3330, 3150, 1675, 1640, 1610, 1545 cm⁻¹ ; (+) APCI MASS: 319(M+H)⁺ ; NMR (DMSO-d₆, δ): 2.7-2.9 (2H, m), 3.64 (2H, s), 3.9-4.1 (2H,m), 7.2-7.3 (5H, m), 7.54 (1H, br s), 7.80 (1H, s), 8.04 (1H, br s).

Preparation 10-4)

6-Carbamoyl-2,3-dihydro-1-(3,4-methylenedioxyphenethyl)-2-oxo-1H-thieno[2,3-b][1,4]thiazine

IR (Nujol): 1650 cm⁻¹ ; (+) APCI MASS: 363 (M+H)⁺ ; NMR (DMSO-d₆, δ):2.7-2.8 (2H, m), 3.64 (2H, s), 3.9-4.1 (2H, m), 5.96 (2H, s), 6.6-6.9(3H, s), 7.52 (1H, br s), 7.77 (1H, s), 8.00 (1H, br s).

Preparation 10-5)

1-Benzyl-6-carbamoyl-2,3-dihydro-2-oxo-1H-thieno[2,3-b]-[1,4]thiazine

IR (Nujol): 1650, 1600 cm⁻¹ ; (+) APCI MASS: 305 (M+H)⁺ ; NMR (DMSO-d₆,δ): 3.78 (2H, s), 5.04 (2H, s), 7.2-7.6 (6H, m), 7.71 (1H, s), 7.89 (1H,br s).

The following compounds were obtained according to a similar manner towhat of Preparation 11-5).

Preparation 11-1)

6-Cyano-2,3-dihydro-1-(3,4-dimethoxyphenethyl)-2-oxo-1H-thieno[2,3-b][1,4]thiazine

IR (Nujol): 2220, 1670 cm⁻¹ ; (+) APCI MASS: 361 (M+H)⁺ ; NMR (DMSO-d₆,δ): 2.6-2.8 (2H, m), 3.6-3.8 (8H, m), 4.0-4.2 (2H, m), 6.6-6.9 (3H, m),7.94 (1H, s).

Preparation 11-2)

6-Cyano-1-cyclohexylmethyl-2,3-dihydro-2-oxo-1H-thieno[2,3-b][1,4]thiazine

IR (Nujol): 2210, 1660 cm⁻¹ ; (+) APCI MASS: 293 (M+H)⁺ ; NMR (DMSO-d₆,δ): 0.8-1.3 (5H, m), 1.5-1.7 (6H, m), 3.7-3.8 (4H, m), 8.11 (1H, s)

Preparation 11-3)

6-Cyano-2,3-dihydro-2-oxo-1-phenethyl-1-thieno[2,3-b][1,4]thiazine

IR (Nujol) 2200, 1660 cm⁻¹ ; (+) APCI MASS: 301 (M+H)⁺ ; NMR (DMSO-d₆,δ): 2.7-2.9 (2H, m), 3.70 (2H, s), 4.0-4.2 (2H, m), 7.1-7.3 (5H, m),7.98 (1H, s).

Preparation 11-4)

6-Cyano-2,3-dihydro-1-(3,4-methylenedioxyphenethyl)-2-oxo-1H-thieno[2,3-b][1,4]thiazine

IR (Nujol): 2210, 1665 cm⁻¹ ; (+) APCI MASS 345 (M+H)⁺ ; NMR (DMSO-d₆,δ): 2.6-2.8 (2H, m), 3.69 (2H, s), 3.9-4.1 (2H, m), 5.95 (2H, s), 6.63(1H, dd, J=1.6, 7.9 Hz), 6.77 (1H, d, J=7.9 Hz), 6.84 (1H, d, J=1.6 Hz),7.99 (1H, s).

Preparation 11-5)

A mixture of1-benzyl-6-carbamoyl-2,3-dihydro-2-oxo-1H-thieno[2,3-b][1,4]thiazine(0.18 g) and p-toluenesulfonyl chloride (0.17 g) in pyridine (5 ml) wasstirred for 24 hours at room temperature. The reaction mixture waspoured into a mixture of ethyl acetate and water, and adjusted to pH 1.5with concentrated hydrochloric acid. The organic layer was successivelywashed with water and brine and dried over magnesium sulfate. Thesolvent was evaporated in vacuo and the residue was purified by columnchromatography on silica gel eluting with chloroform. The fractionscontaining the object compound were collected and evaporated in vacuo togive 1-benzyl-6-cyano-2,3-dihydro-2-oxo-1H-thieno[2,3-b]-[1,4]thiazine(0.11 g)

IR (Film): 2950, 2220, 1670, 1540 cm⁻¹ ; NMR (DMSO-d₆, δ): 3.85 (2H, s),5.12 (2H, s), 7.2-7.4 (5, m), 7.95 (1H, s).

The following compounds were obtained according to a similar manner tothat of Preparation 5-2).

Preparation 12-1)

2,3-Dihydro-1-(3,4-dimethoxyphenethyl)-6-(1-ethoxy-1-iminomethyl)-2-oxo-1-thieno[2,3-b][1,4]thiazinehydrochloride

IR (Nujol): 1662, 1600 cm⁻¹ ; (+) APCI MASS: 407 (M+H)⁺ ; NMR (DMSO-d₆,δ): 1.3-1.5 (3H, m), 2.7-2.9 (2H, m), 3.69 (3H, s), 3.74 (2H, s), 3.76(3H, s), 4.0-4.1 (2H, m), 4.56 (2H, q, J=6.9 Hz), 6.7-7.0 (3H, m), 8.84(1H, s).

Preparation 12-2)

1-Cyclohexylmethyl-2,3-dihydro-6-(1-ethoxy-1-iminomethyl)-2-oxo-1H-thieno[2,3-b][1,4]thiazinehydrochloride

IR (Nujol): 1655, 1600 cm⁻¹ ; (+) APCI MASS: 339 (M+H)⁺ ; NMR (DMSO-d₆,δ): 0.8-1.3 (5H, m), 1.41 (3H, t, J=6.9 Hz), 1.5-1.8 (6H, m), 3.7-3.8(4H, m), 4.5 (2H, q, J=6.9 Hz), 8.81 (1H, s).

Preparation 12-3)

2,3-Dihydro-6-(1-ethoxy-1-iminomethyl)-2-oxo-1-phenethyl-1H-thieno[2,3-b][1,4]thiazinehydrochloride

IR (Nujol): 1665, 1610 cm⁻¹ ; (+) APCI MASS 347 (M+H)⁺ ; NMR (DMSO-d₆,δ): 1.42 (3H, t, J=6.9 Hz), 2.8-2.9 (2H, m), 3.9-4.1 (2H, m), 4.57 (2H,q, J=6.9 Hz), 7.1-7.4 (5H, m), 8.73 (1H, s).

Preparation 12-4)

2,3-Dihydro-6-(1-ethoxy-1-iminomethyl)-1-(3,4-methylenedioxyphenethyl)-2-oxo-1H-thieno[2,3-b][1,4]thiazinehydrochloride

IR (Nujol): 1695, 1670 cm⁻¹ ; (+) APCI MASS: 391 (M+H)⁺ ; NMR (DMSO-d₆,δ): 1.42 (3H, t, J=7.0 Hz), 2.7-2.9 (2H, m), 3.74 (2H, s), 3.9-4.1 (2H,m), 4.58 (2H, q, J=7.0 Hz), 5.95 (2H, s), 6.6-6.9 (2H, m), 6.94 (1H, d,J=1.3 Hz), 8.77 (1H, s).

Preparation 12-5)

1-Benzyl-2,3-dihydro-6-(1-ethoxy-1-iminomethyl)-2-oxo-1H-thieno[2,3-b][1,4]thiazinehydrochloride

(+) APCI MASS: 333 (M+H)⁺ ; NMR (DMSO-d₆, δ): 1.37 (3H, t, J=6.9 Hz),3.89 (2H, s), 4.52 (2H, q, J=6.9 Hz), 5.10 (2H, s), 7.2-7.4 (5H, m),8.73 (1H, s).

Preparation 13-1)

The following compound was obtained according to a similar manner tothat of Preparation 15-6) by using ethoxycarbonylmethyl bromide.

6-Cyano-1-ethoxycarbonylmethyl-2,3-dihydro-2-oxo-1H-thieno[2,3-b[][1,4]thiazine

IR (Nujol): 2210, 1725, 1675 cm⁻¹ ; MASS (z/e): 283 (M+H)⁺ ; NMR(DMSO-d₆, δ): 1.20 (3H, t, J=7.1 Hz), 3.79 (2H, s), 4.13 (2H, q, J=7.1Hz), 4.64 (2H, s), 7.98 (1H, s).

Preparation 13-2)

The following compound was obtained according to a similar manner tothat of Preparation 5-2).

6-(1-Ethoxy-1-iminomethyl)-1-ethoxycarbonylmethyl-2,3-dihydro-2-oxo-1H-thieno[2,3-b][1,4]thiazinehydrochloride

IR (Nujol): 1760, 1690, 1600 cm⁻¹ ; (+) APCI MASS: 329 (M+H)⁺ ; NMR(DMSO-d₆, δ): 1.22 (3H, t, J=7.1 Hz), 1.41 (3H, t, J=7.0 Hz), 3.84 (2H,s), 4.16 (2H, q, J=7.1 Hz), 4.5-4.7 (4H, m), 8.58 (1H, s).

Preparation 14

The following compound was obtained according to a similar manner tothat of Preparation 5-2).

2,3-Dihydro-2-oxo-1H-thieno[2,3-b][1,4]thiazine hydrochloride

(+) APCI MASS: 243 (M+H)⁺ ;

Preparation 15-1)

The following compound was obtained according to a similar manner tothat of Preparation 15-6) by using 2-oxo-1,3-dioxolane.

6-Cyano-2,3-dihydro-1-(2-hydroxyethyl)-2-oxo-1H-thieno[2,3-b][1,4]thiazine

(+) APCI MASS 241 (M+H)⁺ ; NMR (DMSO-d₆, δ): 3.4-3.6 (2H, m), 3.71 (2H,s), 3.8-4.0 (2H, m), 4.83 (1H, t, J=5.5 Hz), 8.01 (1H, s).

Preparation 15-2)

The following compound was obtained according to a similar manner tothat of Preparation 15-6) by using n-butylcarbamoylmethyl bromide.

1-(n-Butylcarbamoylmethyl)-6-cyano-2,3-dihydro-2-oxo-1H-thieno[2,3-b][1,4]thiazine

(+) APCI MASS: 310 (M+H)⁺ ; NMR (DMSO-d₆, δ): 0.8-1.0 (3H, m), 1.1-1.5(4H, m), 3.0-3.2 (2H, m), 3.76 (2H, s), 4.44 (2H, s), 7.78 (1H, s), 8.06(1H, t, J=5.4 Hz).

Preparation 15-3)

The following compound was obtained according to a similar manner tothat of Preparation 15-6) by using 2,2,2-trifluoroethylcarbamoylmethylbromide.

6-Cyano-1-(2,2,2-trifluoroethylcarbamoylmethyl)-2,3-dihydro-2-oxo-1H-thieno[2,3-b][1,4]thiazine

IR (Nujol): 3300, 3100, 2220, 1670, 1580 cm⁻¹ ; NMR (DMSO-d₆, δ): 3.77(2H, s), 3.8-4.1 (2H, m), 4.56 (2H, s), 7.80 (1H, s), 8.84 (1H, t, J=6.2Hz).

Preparation 15-4)

The following compound was obtained according to a similar manner tothat of Preparation 15-6) by using 3-ethoxycarbonylpropyl bromide.

6-Cyano-1-(3-ethoxycarbonylpropyl)-2,3-dihydro-2-oxo-1H-thieno[2,3-b][1,4]thiazine

(+) APCI MASS: 311 (M+H)⁺ ; NMR (DMSO-d₆, δ): 1.18 (3H, t, J=7.1 Hz),1.0-1.3 (2H, m), 2.32 (2H, t, J=7.3 Hz), 3.72 (2H, s), 3.8-3.9 (2H, m),4.05 (2H, q, J=7.1 Hz), 8.06 (1H, s).

Preparation 15-5)

The following compound was obtained according to a similar manner tothat of Preparation 15-6) by using3,4-methylenedioxyphenylcarbamoylmethyl bromide.

6-Cyano-2,3-dihydro-1-(3,4-methylenedioxyphenyl-carbamoylmethyl)-2-oxo-1H-thieno[2,3-b][1,4]thiazine

IR (Nujol): 2210, 1670, 1540 cm⁻¹ ; (+) APCI MASS: 374 (M+H)⁺ ; NMR(DMSO-d₆, δ): 3.79 (2H, s), 4.64 (2H, s), 5.98 (2H, s), 6.86 (1H, d,J=8.4 Hz), 6.95 (1H, dd, J=1.9, 8.4 Hz), 7.28 (1H, d, J=1.9 Hz), 7.95(1H, s), 10.18 (1H, s).

Preparation 15-6)

To a solution of 6-cyano-2,3-dihydro-2-oxo-1H-thieno[2,3-b][1,4]thiazine(13.6 g) in N,N-dimethylformamide (270 ml) was added potassiumtert-butoxide (9.3 g) under ice cooling. After stirring for 10 minutesunder ice cooling, to the reaction mixture was added 1-iodobutane (9.5ml). After stirring for 8 hours at room temperature, the reactionmixture was poured into a mixture of ethyl acetate and water. Theorganic layer was successively washed with water and brine and driedover magnesium sulfate. The solvent was evaporated in vacuo and theresidue was purified by column chromatography on silica gel eluting withchloroform. The fractions containing the object compounds were collectedand evaporated in vacuo to give1-n-butyl-6-cyano-2,3-dihydro-2-oxo-1H-thieno[2,3-b][1,4]thiazine (13.78g).

IR (Nujol): 2200, 1660, 1540 cm⁻¹ ; (+) APCI MASS: 253 (M+H)⁺ ; NMR(DMSO-d₆, δ): 0.87 (3H, t, J=7.2 Hz), 1.2-1.6 (4H, m), 3.71 (2H, s),3.8-3.9 (2H, m), 8.07 (1H, s).

The following compounds were obtained according to a similar manner tothat of Preparation 5-2).

Preparation 16-1)

2,3-Dihydro-6-(1-ethoxy-1-iminomethyl)-1-(2-hydroxyethyl)-2-oxo-1H-thieno[2,3-b][1,4]thiazinehydrochloride, which was used in the next reaction without furtherpurification.

Preparation 16-2)

1-(n-Butylcarbamoylmethyl)-2,3-dihydro-6-(1-ethoxy-1-iminomethyl)-2-oxo-1H-thieno[2,3-b][1,4]thiazinehydrochloride

(+) APCI MASS: 356 (M+H)⁺ ; NMR (DMSO-d₆, δ): 0.8-0.9 (3H, m), 1.2-1.5(7H, m), 3.0-3.2 (2H, m), 3.81 (2H, s), 4.42 (2H, s), 4.57 (2H, q, J=6.9Hz), 8.20 (1H, t, J=5.5 Hz), 8.38 (1H, s).

Preparation 16-3)

1-(2,2,2-Trifluoroethylcarbamoylmethyl)-2,3-dihydro-6-(1-ethoxy-1-iminomethyl)-2-oxo-1H-thieno[2,3-b][1,4]thiazinehydrochloride

IR (Nujol): 3250, 1705, 1675, 1590, 1550 cm⁻¹ ; (+) APCI MASS: 382(M+H)⁺ ; NMR (DMSO-d₆, δ): 1.41 (3H, t, J=7.0 Hz), 3.4-4.1 (4H, m),4.4-4.7 (4H, m), 8.40 (1H, s), 8.8-9.1 (1H, m).

Preparation 16-4)

1-(3-Ethoxycarbonylpropyl)-2,3-dihydro-6-(1-ethoxy-1-iminomethyl)-2-oxo-1H-thieno[2,3-b][1,4]thiazinehydrochloride

(+) APCI MASS: 357 (M+H)⁺ ; NMR (DMSO-d₆, δ): 1.17 (3H, t, J=7.1 Hz),1.41 (3H, t, J=6.9 Hz), 1.7-1.9 (2H, m), 2.37 (2H, t, J=7.5 Hz), 3.77(2H, s), 3.89 (2H, t, J=7.1 Hz), 4.04 (2, q, J=7.1 Hz), 4.57 (2H, q,J=6.9 Hz), 8.83 (1H, s).

Preparation 16-5)

2,3-Dihydro-6-(1-ethoxy-1-iminomethyl)-1-(3,4-methylenedioxyphenylcarbamoylmethyl)-2-oxo-1H-thieno[2,3-b][1,4]thiazinehydrochloride

(+) APCI MASS: 420 (M+H)⁺ ; NMR (DMSO-d₆, δ): 1.41 (3H, t, J=7.1 Hz),3.84 (2H, s), 4.5-4.7 (4H, m), 5.98 (2H, s), 6.86 (1H, d, J=8.4 Hz),7.00 (1H, dd, J=2.0, 8.4 Hz), 7.2-7.4 (1H, m), 8.50 (1H, s), 10.44 (1H,s)

Preparation 16-6)

1-n-Butyl-2,3-dihydro-6-(1-ethoxy-1-iminomethyl)-2-oxo-1H-thieno[2,3-b][1,4]thiazinehydrochloride

IR (Nujol): 1680, 1605 cm⁻¹ ; (+) APCI MASS: 299 (M+H)⁺ ; NMR (DMSO-d₆,δ): 0.89 (3H, t, J=7.2 Hz), 1.2-1.6 (7H, m), 3.75 (2H, s), 3.8-3.9 (2H,m), 4.58 (2H, q, J=7.0 Hz), 8.82 (1H, s).

Preparation 17

Under nitrogen atmosphere, potassium hydroxide (147 mg) in dimethylsulfoxide (10 ml) was stirred at room temperature for 30 minutes. To thesolution were added2,3-dihydro-6-methoxycarbonyl-2-oxothieno[2,3-b][1,4]thiazine (0.50 g),sodium iodide (0.39 g) and 2-chloroethyl methyl sulfide (0.26 ml), andthe mixture was stirred at 50° C. for 6.5 hours. The mixture was pouredinto water and extracted with ethyl acetate. The organic layer waswashed with water and brine, dried over anhydrous sodium sulfate andevaporated under reduced pressure. The residue was purified by columnchromatography on silica gel (eluent: hexane:ethyl acetate=3:1) to give2,3-dihydro-6-methoxycarbonyl-1-(2-(methylthio)-ethyl]-2-oxothieno[2,3-b][1,4]thiazine(463 mg).

NMR (DMSO-d₆, δ): 2.08 (3H, s), 2.62 (2H, t, J=7.2 Hz), 3.71 (2H, s),4.10 (2H, t, J=6.9 Hz), 7.86 (1H, s).

Preparation 18-1)

Sodium borohydride (0.17 g) was added into a mixture of6-ethoxycarbonyl-4,5,6-7-tetrahydro-4-oxobenzo[b]thiophene (1.00 g) andmethanol (MeOH) (20 ml) in a portion at room temperature (r.t.) undernitrogen atmosphere, and the mixture was stirred at room temperature for30 minutes. The reaction mixture was added into a mixture of ethylacetate (AcOEt) and water, and was adjusted to pH 1.6 with 6 Nhydrochloric acid (HCl). The separated organic layer was washed with asaturated aqueous solution of sodium hydrogen carbonate (sat. NaHCO₃aq.), water, and brine, and dried over magnesium sulfate (MgSO₄), andthen evaporated in vacuo. After evaporation of the filtrate, theresulting oil was purified by chromatography on silica gel (chloroform(CHCl₃)-MeOH as eluent) to give6-ethoxycarbonyl-4-hydroxy-4,5,6,7-tetrahydrobenzo[b]thiophene (0.79 g)as an oil.

IR (KBr): 3433, 1730 cm⁻¹ ; APCI MASS: 225 (M-H); NMR (CDCl₃, δ): 1.27(3H, t, J=7.1 Hz), 1.96 (2H, m), 2.18 (2H, m), 2.99 (1H, m), 4.22 (2H,q, J=7.1 Hz), 6.1 (1H, t J=6.1 Hz), 7.06 (1H, d, J=5.2 Hz), 7.12 (1H, d,J=5.2 Hz).

Process 18-2)

Acetic anhydride (4.1 ml) was added to a mixture of6-ethoxycarbonyl-4-hydroxy-4,5,6,7-tetrahydrobenzo[b]thiophene (2.06 g)and pyridine (8 ml) under water cooling, and was stirred at r.t. for 2.5hours. The reaction mixture was added into a mixture of AcOEt and water,and was adjusted to pH 1.6 with 6N HCl. The separated organic layer waswashed with a saturated aqueous solution of sodium hydrogen carbonate(sat. NaHCO₃ aq.), water, and brine, and dried over MgSO₄, and thenevaporated in vacuo to give4-acetoxy-6-ethoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophene (2.36 g)as an oil.

APCI MASS: 269 (M+H); NMR (CDCl₃, δ): 1.29 (3H, t, J=7.1 Hz), 2.09 (3H,s), 1.9-2.6 (2H, m), 2.95-3.2 (3H, m), 4.22 (2H, q, J=7.1 Hz), 6.05 (1H,m), 6.82 (1H, d, J=5.2 Hz), 7.10 (1H, d, J=5.2 Hz).

Preparation 18-3)

A mixture of4-acetoxy-6-ethoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophene (2.34 g),tosic acid monohydrate (0.13 g), and toluene (50 ml) was stirred atreflux for 2 hours. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, and then the separatedorganic layer was washed with a saturated aqueous solution of sodiumhydrogen carbonate, water, and brine, and dried over MgSO₄, and thenevaporated in vacuo. After evaporation of the filtrate, the resultingoil was purified by chromatography on silica gel (CHCl₃ -MeOH as eluent)to give 6-ethoxycarbonyl-6,7-dihydrobenzo[b]thiophene (1.03 g) as anoil.

APCI MASS: 209 (M+H); NMR (CDCl₃, δ): 1.30 (3H, t, J=7.1 Hz), 3.10 and3.13 (2H, each s), 3.4-3.7 (1H, m), 4.15 (2H, q, J=7.1 Hz), 5.90 (1H,dd, J=9.6, 3.4 Hz), 6.53 (1H, dd, J=9.6, 3.4 Hz), 6.83 (1H, d, J=5.1Hz), 7.03 (1H, d, J=5.1 Hz).

Preparation 18-4)

A mixture of 6-ethoxycarbonyl-6,7-dihydrobenzo[b]thiophene (1.00 g), 10%palladium on carbon (2.16 g), AcOEt (30 ml) an, MeOH (10 ml) was stirredat r.t. under hydrogen atmosphere for 4 hours. After removal ofinsoluble solids, the filtrate was concentrated in vacuo to give6-ethoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophene (0.96 g) as an oil.

IR (Neat): 2935, 1730, 1596 cm⁻¹ ; APCI MASS: 211 (M+H); NMR (CDCl₃, δ):1.28 (3H, t, J=7.1 Hz), 1.6-2.4 (3H, m), 2.6-3.3 (4H, m), 4.14 (2H, q,J=7.1 Hz), 6.75 (1H, d, J=5.1 Hz), 7.07 (1H, d, J=5.1 Hz).

Preparation 18-5)

A mixture of 6-ethoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophene (0.80g) and dichloromethane (CH₂ Cl₂) was dropwise added to a mixture ofaluminum chloride (AlCl₃) (1.01 g) and CH₂ Cl₂ (5 ml) under ice-watercooling, and was stirred under the same conditions for 15 minutes. Amixture of 1,1-dichloromethyl methyl ether (0.52 ml) and CH₂ Cl₂ (3 ml)was thereto added, and was stirred under the same conditions for 10minutes. The reaction mixture was added into a mixture of CHCl₃, ice,and water. The separated organic layer was washed with water, and brine,and dried over MgSO₄. After evaporation of the filtrate, the resultingoil was purified by chromatography on silica gel (n-hexane-AcOEt aseluent) to give6-ethoxycarbonyl-2-formyl-4,5,6,7-tetrahydrobenzo[b]thiophene (0.33 g).

IR (Neat): 2935, 1730, 1596 cm⁻¹ ; APCI MASS: 239 (M+H); NMR (CDCl₃, δ):1.26 (3H, t, J=7.1 Hz), 1.6-2.4 (3H, m), 2.6-3.3 (4H, m), 4.16 (2H, q,J=7.1 Hz), 7.43 (1H, s), 9.80 (1H, s).

Preparation 18-6)

A mixture of6-ethoxycarbonyl-2-formyl-4,5,6,7-tetrahydrobenzo[b]thiophene (3.23 g),hydroxylamine hydrochloride (0.92 g), and ethanol (EtOH) (30 ml) wasstirred at reflux for 30 minutes. The reaction mixture was added into amixture of AcOEt and water. The separated organic layer was washed withwater, and brine, and dried over MgSO₄. After evaporation of thefiltrate, the resulting precipitate was washed with a mixture ofn-hexane and isopropyl ether to give6-ethoxycarbonyl-2-hydroxyimino-4,5,6,7-tetrahydrobenzo[b]thiophene(1.81 g).

APCI MASS: 254 (M+H); NMR (DMSO-d₆, δ): 1.26 (3H, t, J=7.1 Hz), 1.6-3.2(7H, m), 4.14 (2H, q, J=7.1 Hz), 7.11 (1H, s), 7.67 (1H, s).

Preparation 18-7)

A mixture of6-ethoxycarbonyl-2-hydroxyimino-4,5,6,7-tetrahydrobenzo[b]thiophene(1.77 g) and acetic anhydride (0.84 ml) was stirred at reflux for 45minutes. The reaction mixture was added into a mixture of AcOEt andwater. The separated organic layer was washed with water, and brine, anddried over MgSO₄. After evaporation of the filtrate, the resultingprecipitate was washed with n-hexane to give6-ethoxycarbonyl-2-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene (1.28 g).

IR (Neat): 2937, 2212, 1724 cm⁻¹ ; APCI MASS: 236 (M+H); NMR (DMSO-d₆,δ): 1.26 (3H, t, J=7.1 Hz), 1.6-3.2 (7H, m), 4.14 (2H, q, J=7.1 Hz),7.66 (1H, s).

Preparation 18-8)

A mixture of6-ethoxycarbonyl-2-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene (1.26 g),and EtOH (10 ml) was bubbled with hydrogen chloride with ice-watercooling. After being saturated with hydrogen chloride, the mixture wasstirred at r.t. for 3 hours. The reaction mixture was evaporated to giveprecipitate. The resulting precipitate was washed with diethyl ether(Et₂ O) to give 6-ethoxycarbonyl2-(1-ethoxy-1-iminomethyl)-4,5,6,7-tetrahydrobenzo[b]thiophenehydrochloride (1.55 g).

NMR (DMSO-d₆, δ): 1.16 (3H, t, J=7.1 Hz), 1.26 (3H, t, J=7.1 Hz),1.6-3.2 (7H, m), 4.11 (2H, q, J=7.1 Hz), 4.58 (2H, q, J=7.1 Hz), 8.22(1H, s).

Preparation 19-1)

The following compound was obtained according to a similar manner tothat of Preparation 20-1).

2-(Methoxycarbonylmethylthio)-5-cyano-3-nitrothiophene

NMR (DMSO-d₆, δ): 3.75 (3H, s), 4.37 (2H, s), 8.61 (1H, s).

Preparation 19-2)

The following compound was obtained according to a similar manner tothat of Preparation 20-2).

6-Cyano-2,3-dihydro-2-oxothieno[2,3-b][1,4]thiazine

NMR (DMSO-d₆, δ): 3.64 (2H, s), 7.45 (1H, s), 10.85 (1H, s).

Preparation 20-1)

To a mixture of 2-bromo-5-methoxycarbonyl-3-nitrothiophene (110.7 g) andmethyl mercaptoacetate (37.2 ml) in tetrahydrofuran (1 l) was addedtriethylamine (63.8 ml). After stirring for 4 hours at room temperature,the reaction mixture was poured into water. The resulting precipitatewas collected by filtration and washed with water to give2-methoxycarbonylmethylthio-5-methoxycarbonyl-3-nitrothiophene (118.15g).

NMR (DMSO-d₆, δ): 3.74 (3H, s), 3.86 (3H, s), 4.37 (2H, s), 8.16 (1H,s).

Preparation 20-2)

To a solution of2-methoxycarbonylmethylthio-5-methoxycarbonyl-3-nitrothiophene (26.1 g)in acetic acid (360 ml) and water (36 ml) was added portionwise iron(36.5 g) at 80° C. After stirring for 3 hours at 80° C., the hotreaction mixture was filtered and the filtrate was poured intoice-water. The resulting precipitate was collected by filtration andwashed with water to give2,3-dihydro-6-methoxycarbonyl-2-oxothieno[2,3-b][1,4]thiazine (11.12 g).

NMR (DMSO-d₆, δ): 3.63 (2H, s), 3.80 (3H, s), 7.31 (1H, s).

Preparation 21-1)

The following compound was obtained according to a similar manner tothat of Preparation 6-2).

6-Cyano-2,3-dihydrothieno[2,3-b][1,4thiazine

NMR (DMSO-d₆, δ): 3.0-3.1 (2H, m), 3.4-3.6 (2H, m), 6.0-6.2 (1H, m),7.23 (1H, s).

Preparation 21-2)

The following compound was obtained according to a similar manner tothat of Preparation 23-1)

6-Cyano-2,3-dihydro-1-(ethoxycarbonylacetyl)thieno-[2,3-b][1,4]thiazine

IR (Nujol): 2220, 1740, 1660 cm⁻¹ ; (+) APCI MASS: 297 (M+H)⁺ ; NMR(DMSO-d₆, δ): 1.0-1.3 (3H, m), 3.2-3.5 (2H, m), 3.80 (2H), s), 3.9-4.3(4H, m), 8.19 (1H, s).

Preparation 21-3)

The following compound was obtained according to a similar manner tothat of Preparation 5-2).

Ethyl2,3-dihydro-1-(ethoxycarbonylacetyl)-6-(1-ethoxy-1-iminomethyl)thieno[2,3-b][1,4]thiazinehydrochloride

(+) APCI MASS: 343 (M+H)⁺ ; NMR (DMSO-d₆, δ): 1.1-1.5 (6H, m), 3.3-4.2(8H, m) 4.58 (2H, q, J=7.0 Hz), 8.80 (1H, s).

Preparation 22-1)

The following compound was obtained according to a similar manner tothat of Preparation 6-2).

2,3-Dihydro-6-methoxycarbonylthieno[2,3-b][1,4]thiazine

IR (Nujol): 3350, 1680, 1565 cm⁻¹ ; (+) APCI MASS: 216 (M+H)⁺ ; NMR(DMSO-d₆, δ): 3.0-3.1 (2H, m), 3.4-3.5 (2H, m), 3.75 (3H, s), 5.9-6.0(1H, m), 7.13 (1H, s).

Preparation 22-2)

The following compound was obtained according to a similar manner tothat of Preparation 23-1).

1-Benzoyl-2,3-dihydro-6-methoxycarbonylthieno[2,3-b][1,4]thiazine

IR (Nujol): 1690, 1640 cm⁻¹ ; (+) APCI MASS: 320 (M+)⁺ ; NMR (DMSO-d₆,δ): 3.3-3.4 (2H, m), 3.76 (3H, s), 3.9-4.1 (2H, m), 7.4-7.8 (6H, m).

Preparation 22-3)

The following compound was obtained according to a similar manner tothat of Preparation 3-3).

1-Benzoyl-6-carboxy-2,3-dihydrothieno[2,3-b][1,4]thiazine

IR (Nujol): 1635 cm⁻¹ ; (+) APCI MASS: 306 (M+H)⁺ ; NMR (DMSO-d₆, δ):3.2-3.4 (2H, m), 3.9-4.1 (2H, m), 7.4-7.6 (6H, m), 13.05 (1H, s).

Preparation 22-4)

The following compound was obtained according to a similar manner tothat of Preparation 3-7).

1-Benzoyl-6-carbamoyl-2,3-dihydrothieno[2,3-b][1,4]thiazine

IR (Nujol): 1660, 1620 cm⁻¹ ; (+) APCI MASS: 305 (M+H)⁺ ; NMR (DMSO-d₆,δ): 3.3-3.4 (2H, m), 3.9-4.0 (2H, m), 7.28 (1H, br s), 7.4-7.6 (5H, m),7.7-8.0 (2H, m).

Preparation 22-5)

The following compound was obtained according to a similar manner tothat of Preparation 11-5).

1-Benzoyl-6-cyano-2,3-dihydrothieno[2,3-b][1,4]thiazine

IR (Nujol): 2220, 1640 cm⁻¹ ; (+) APCI MASS: 287 (M+H)⁺ ; NMR (DMSO-d₆,δ): 3.3-3.4 (2H, m), 3.9-4.1 (2H, m), 7.4-7.6 (5H, m), 7.80 (1H, s).

Preparation 22-6)

The following compound was obtained according to a similar manner tothat of Preparation 5-2).

1-Benzoyl-6-(1-ethoxy-1-iminomethyl)-2,3-dihydrothieno-[2,3-b][1,4]thiazinehydrochloride

(+) APCI MASS: 333 (M+F)⁺ ; NMR (DMSO-d₆, δ): 1.3-1.5 (3H, m), 3.3-3.5(2H, m), 3.9-4.0 (2H, m), 4.56 (2H, q, J=7.0 Hz), 7.4-7.6 (5H, m), 8.53(1H, s).

Preparation 23-1)

To a mixture of 6-cyano-2,3-dihydrothieno[2,3-b][1,4]-thiazine (0.3 g)and triethylamine (0.46 ml) in dichloromethane (10 ml) was dropwiseadded acetyl chloride (0.23ml). After stirring for 5 hours at roomtemperature, the reaction mixture was poured into a mixture of ethylacetate and water. The organic layer was successively washed with brineand dried over magnesium sulfate. The solvent was evaporated in vacuoand the residue was pulverized from diisopropyl ether to give1-acetyl-6-cyano-2,3-dihydrothieno-[2,3-b][1,4]thiazine (0.33 g).

IR (Nujol): 2200, 1660 cm⁻¹ ; NMR (DMSO-d₆, δ): 2.21 (3H, s), 3.2-3.4(2H, m) 3.9-4.0 (2H, m), 8.18 (1H, s).

Preparation 23-2)

The following compound was obtained according to a similar manner tothat of Preparation 5-2).

1-Acetyl-6-(1-ethoxy-1-iminomethyl)-2,3-dihydrothieno-[2,3-b][1,4]thiazinehydrochloride

IR (Nujol): 1665, 1595 cm⁻¹ ; (+) APCI MASS: 271 (M+H)⁺ ; NMR (DMSO-d₆,δ): 1.3-1.5 (3H, m), 2.26 (3H, s), 3.2-3.5) (2H, m), 3.9-4.1 (2H, m),4.5-4.7 (2H, m), 8.81 (1H, s).

Preparation 24-1)

The following compound was obtained according to a similar manner tothat of Preparation 15-6).

2,3-Dihydro-1-ethyl-6-methoxycarbonyl-2-oxothieno-[2,3-b][1,4]thiazine

IR (Nujol): 1700, 1650 cm⁻¹ ; NMR (DMSO-d₆, δ): 1.08 (3H, t, J=7.1 Hz),3.69 (2H, s), 3.83 (3H, s), 3.92 (2H, q, J=7.1 Hz), 7.77 (1H, s).

Preparation 24-2)

The following compound was obtained according to a similar manner tothat of Preparation 6-2).

2,3-Dihydro-1-ethyl-6-methoxycarbonylthieno[2,3-b][1,4]thiazine

IR (Nujol): 2950, 1700, 1550 cm⁻¹ ; (+) APCI MASS: 244 (M+H)⁺ ; NMR(DMSO-d₆, δ): 1.02 (3H, t, J=7.0 Hz), 3.1-3.5 (6H, m), 3.76 (3H, s),7.41 (1H, s).

EXAMPLE 1

To a mixture of ammonium chloride (NH₄ Cl) (66.5 mg) and toluene (3 ml)was dropwise added 2 M trimethylalminum (AlMe₃) (0.62 ml) under nitrogenatmosphere at r.t, and the mixture was stirred at r.t. for 1 hour. Tothe reaction mixture was added a mixture of4-(N-butylcarbamoylmethylidene)-2-methoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophene (95.6 mg) and toluene (2 ml). Thereaction mixture was stirred at reflux for 8 hours. After being allowedto cool at room temperature, the reaction mixture was poured into amixture of chloroform (CHCl₃) and MeOH. After removal of insolublesolids, the filtrate was evaporated in vacuo. The resulting residue waspurified by chromatography on silica gel (CHCl₃ -MeOH as an eluent). Thefractions including the object compound were collected and evaporated invacuo. The resulting precipitate was washed with Et₂ O to give4-(N-butylcarbamoylmethylidene)-2-amidino-4,5,6,7-tetrahydrobenzo[b]thiophene(39.8 mg).

mp: 114-117° C. IR, (KBr): 3274, 1648, 1558, 1540, 1508 cm⁻¹ ; MASS(z/e): 292 (M+H)⁺ ; of free; NMR (DMSO-d₆, δ): 0.88 (2H, t, J=6.9 Hz),1.2-1.6 (4H, m), 1.87 (2H, m), 2.94 (2H, t, J=5.6 Hz), 3.0-3.2 (4H, m),6.30 (1H, s), 8.05 (1H, t, J=7.5 Hz), 8.37 (1H, s), 9.31 (4H, s).

EXAMPLE 2-1)

The following compound was obtained according to a similar manner tothat of Example 1.

2-Amidino-4-n-butylidene-4,5,6,7-tetrahydrobenzo[b]thiophenehydrochloride

mp: 115-118° C. IR (KBr): 3085, 1660, 1564, 1504 cm⁻¹ ; MASS (z/e): 235(M+H)⁺ of free; NMR (DMSO-d₆, δ): 0.88 (3H, m), 1.3-3.0 (10H, m), 5.67and 5.95 (1H, each t, J=7.2 Hz), 8.10 and 8.39 (1H, each s), 9.14 and9.32 (4H, each s).

EXAMPLE 2-2)

The following compound was obtained according to a similar manner tothat of Example 4-2).

2-Amidino-4-n-butyl-4,5,6,7-tetrahydrobenzo[b]thiophene trifluoroacetate

mp: 235-238° C. IR (KBr): 3,305, 3093, 2937, 1668, 1597, 1512 cm⁻¹ ;MASS (z/e): 237 (M+H)⁺ of free; NMR (DMSO-d₆, δ): 0.91 (3H, m), 1.2-3.0(13H, m), 7.91 (1H, s), 9.01 and 9.10 (4H, each s).

EXAMPLE 3

A mixture of4-n-butylidene-2-(1-ethoxy-1-iminomethyl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophenehydrochloride (0.34 g), 2.7 N ethanol solution of ammonia (1.00 ml) andEtOH (20 ml) was stirred at reflux for 6 hours. After evaporation, theresulting oil was purified by chromatography on silica gel (CHCl₃ -MeOHas an eluent). The fractions including the object compound werecollected and evaporated in vacuo. The resulting syrup was dissolvedwith a mixture of 0.1% TFA aqueous solution and acetonitrile (CH₃ CN),and lyophilized to give2-amidino-4-n-butylidene-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophenetrifluoroacetate (84.2 mg).

mp: 91-94° C. IR (KBr): 3087, 1660, 1564, 1504 cm⁻¹ ; MASS (z/e): 249(M+H)⁺ of free; NMR (DMSO-d₆, δ): 0.7-2.4 (13H, m), 2.89 (2H, t, J=6.1Hz), 5.71 and 5.89 (1H, each t, J=7.4 Hz (at 5.71) and 5.8 (at 5.89)),8.00 and 8.12 (1H, each s), 9.11, 9.26, and 9.33 (4H, each s).

EXAMPLE 4-1)

The following compound was obtained according to a similar manner tothat of Example 1.

2-Amidino-4-n-butylidene-4,5,6,7-tetrahydrobenzo[b]furan hydrochloride

mp: 156-160° C. IR (KRr): 3336, 3101, 1672, 1612, 1556 cm⁻¹ ; MASS(z/e): 219 (M+H)⁺ of free; NMR (DMSO-d₆, δ): 0.90 (3H, t, J=7.4 Hz),1.38 (2H, q, J=7.4 Hz), 1.90 (2H, m), 2.14 (2H, q, J=7.4 Hz), 2.38 (2,m), 2.78 (2H, t, J=6.3 Hz), 5.36 and 5.63 (1H, each t, J=7.4 Hz), 8.06(1H, s), 9.12 and 9.37 (4H, each br s).

EXAMPLE 4-2)

A mixture of 2-amidino-4-n-butylidene-4,5,6,7-tetrahydrobenzo[b]furanhydrochloride (107.3 mg), 10% Pd on carbon, and MeOH (1 ml) was stirredat r.t. under hydrogen (H₂) atmosphere for 2 hours. After removal of thecatalyst, the filtrate was evaporated, and dissolved in a mixture ofacetonitrile (CH₃ CN) and 0.1% aqueous trifluoroacetic acid (TFA aq).The solution was subjected to preparative High Performance LiquidChromatography (HPLC) under the following condition:

Preparative HPLC condition:

Column: YMC-PACK-ODS-15 S-15 120A 50.o slashed.×250 mm; Eluent: 40% CH₃CN in 0.1% TFA aq; Flow: 118 ml/minutes.

Fractions including the object compound were combined, concentrated invacuo, and lyophilized to give2-amidino-4-butyl-4,5,6,7-tetrahydrobenzo[b]furan (0.05 g).

mp: 243-245° C. IR (KBr): 3305, 3104, 2937, 1672, 1569 cm⁻¹ ; MASS(z/e): 221 (M+H)⁺ of free; NMR (DMSO-d₆, δ): 0.90 (3H, m), 1.2-2.2 (11H,m), 2.80 (2H, m), 7.65 (1H, s), 8.88 and 9.09 (4H, each s).

EXAMPLE 5

The following compound was obtained according to a similar manner tothat of Example 3.

6-Amidino-1-butyl-2,3-dihydro-2-oxo-1H-thieno[2,3-b][1,4]thiazine4,4-dioxide hydrochloride

IR (Nujol): 1670, 1550, 1510 cm⁻¹ ; (+) APCI MASS: 302 (M+H)⁺ ; NMR(DMSO-d₆, δ): 0.89 (3H, t, J=7.2 Hz), 1.2-1.7 (4H, m), 3.9-4.1 (2H, m),5.05 (2H, s), 8.37 (1H, s), 9.50 (4H, br s); Elemental Analysis for C₁₁H₁₆ ClN₃ O₃ S₂.1.6H₂ O; Calcd.: C; 36.03, H; 5.28, N; 11.46; Found: C;36.01, H; 5.07, N; 11.30.

EXAMPLE 6

The following compound was obtained according to a similar manner tothat of Example 1.

6-Amidino-1-butyl-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazinetrifluoroacetate

IR (Nujol): 1655, 1570, 1505 cm⁻¹ ; (+) APCI MASS: 256 (M+H)⁺ ; NMR(DMSO-d₆, δ): 0.92 (3H, t, J=7.2 Hz), 1.2-1.6 (4H, m), 3.1-3.3 (4H, m),3.4-3.6 (2H, m), 7.73 (1H, s), 9.01 (4H, br s).

EXAMPLE 7

The following compound was obtained according to a similar manner tothat of Example 1.

6-Amidino-1-benzyl-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazinehydrochloride

IR (Nujol): 1650, 1570, 1500 cm⁻¹ ;

(+) APCI MASS: 290 (M+H)⁺ ; NMR (DMSO-d₆, δ): 3.0-3.2 (2H, m), 3.4-3.6(2H, m), 4.4-4.6 (2H, m), 7.2-7.5 (5H, m), 8.07 (1H, s), 9.06 (4H, brs).

The following compounds were obtained according to a similar manner tothat of Example 3.

EXAMPLE 8-1)

6-Amidino-2,3-dihydro-1-(3,4-dimethoxyphenethyl)-2-oxo-1H-thieno[2,3-b][1,4]thiazinehydrochloride

mp: 133-135° C. IR (Nujol): 1660, 1565, 1505 cm⁻¹ ; (+) APCI MASS: 378(M+H)⁺ ; NMR (DMSO-d₆, δ): 2.7-2.9 (2H, ) 3.69 (3H, s), 3.72 (2H, s),3.74 (3H, s), 4.0-4.2 (2H, m), 6.7-6.9 (3H, m), 8.29 (1H, s), 9.28 (4H,br s); Elemental Analysis for C₁₇ H₂₀ ClN₃ O₃ S₂.1.2H₂ O; Calcd.: C;46.88, H; 4 5.18, N; 9.65; Found: C; 46.60, H; 4.74, N; 9.43.

EXAMPLE 8-2)

6-Amidino-1-cyclohexylmethyl-2,3-dihydro-2-oxo-1H-thieno[2,3-b][1,4]thiazinehydrochloride

mp: >250° C. IR (Nujol): 1665, 1565 cm⁻¹ ; (+) APCI MASS: 310 (M+H)⁺ ;NMR (DMSO-d₆, δ): 0.8-1.2 (5H, m), 1.5-1.8 (6H, m), 3.7-3.8 (4H, m),8.27 (1H, s), 9.30 (4H, br s); Elemental Analysis for C₁₄ H₂₀ ClN₃OS₂.1.3H₂ O; Calcd.: C; 45.53, H; 6.17, N; 11.38; Found: C; 45.51, H;6.14, N; 11.14.

EXAMPLE 8-3)

6-Amidino-2,3-dihydro-2-oxo-1-phenethyl-1H-thieno-[2,3-b][1,4]thiazinehydrochloride

mp: >250° C. IR (Nujol): 3350, 1675, 1630, 1570 cm⁻¹ ; (+) APCI MASS:318 (M+H)⁺ ; NMR (DMSO-d₆, δ): 2.8-3.0 (2H, m), 3.73 (2H, s), 4.0-4.2(2H, m), 7.1-7.4 (5H, m), 8.27 (1H, s), 9.33 (4H, br s); ElementalAnalysis or C₁₅ H₁₆ ClN₃ OS₂.0.2H₂ O; Calcd.: C; 50.40, H; 4.62, N;11.75; Found: C; 50.36, H; 4.54, N; 11.62.

EXAMPLE 8-4)

6-Amidino-2,3-dihydro-1-(3,4-methylenedioxyphenethyl)-2-oxo-1H-thieno[2,3-b][1,4]thiazinehydrochloride

mp: 161-162° C. IR (Nujol): 1660, 1565, 1500 cm⁻¹ ; (+) APCI MASS: 362(M+H)⁺ ; NMR (DMSO-d₆, δ): 2.7-2.9 (2H, m), 3.72 (2H, s), 3.9-4.2 (2H,m), 5.96 (2H, s), 6.6-7.0 (3H, m), 8.25 (1H, s), 9.30 (4H, br s);Elemental Analysis for C₁₆ H₁₆ ClN₃ O₃ S₂.1.0H₂ O; Calcd.: C; 6.21, H;4.36, N; 10.10; Found: C; 46.03, H; 4.02, N; 9.69.

EXAMPLE 8-5)

6-Amidino-1-benzyl-2,3-dihydro-2-oxo-1H-thieno[2,3-b]-[1,4]thiazinehydrochloride

mp: 164-166° C. IR (Nujol): 1665, 1570 cm⁻¹ ; (+) APCI MASS: 304 (M+H)⁺; NMR (DMSO-d₆, δ): 3.88 (2H, s), 5.10 (2H, s), 7.2-7.4 (5H, m), 8.26(1H, s), 9.25 (4H, br s); Elemental Analysis for C₁₄ H₁₄ ClN₃ OS₂.1.2H₂O; Calcd.: C; 46.52, H; 4.57, N; 11.62; Found: C; 46.52, H; 4.18, N;11.58.

EXAMPLE 9-1)

The following compound was obtained according to a similar manner tothat of Example 3.

6-Amidino-1-ethoxycarbonylmethyl-2,3-dihydro-2-oxo-1H-thieno[2,3-b][1,4]thiazinehydrochloride

IR (Nujol): 3380, 1735, 1660, 1570 cm⁻¹ ; (+) APCI MASS: 300 (M+H)⁺ ;NMR (DMSO-d₆, δ): 1.22 (3H, t, J=7.1 Hz), 3.82 (2H, s), 4.16 (2H, q,J=7.1 Hz), 4.63 (2H, s), 8.11 (1H, s), 9.24 (4H, br s).

EXAMPLE 9-2)

A mixture of6-amidino-1-ethoxycarbonylmethyl-2,3-dihydro-2-oxo-1H-thieno[2,3-b][1,4]thiazinehydrochloride (0.15 g) and CHCl (1.5 ml) was stirred at 80° C. for 7hours. The reaction mixture was evaporated in vacuo. The resulting oilwas dissolved with water, and lyophilized to give6-amidino-1-carboxymethyl-2,3-dihydro-2-oxo-1H-thieno[2,3-b][1,4]thiazinehydrochloride (90.6 mg).

IR (Nujol). 1715, 1665, 1575 cm⁻¹ ; (+) APCI MASS: 272 (M+H)⁺ ; NMR(DMSO-d₆, δ): 3.81 (2H, s), 4.54 (2H, s), 8.09 (1H, s), 9.10 and 9.37(4H, each s).

EXAMPLE 10

The following compound was obtained according to a similar manner tothat of Example 3.

6-Amidino-2,3-dihydro-2-oxo-1H-thieno[2,3-b][1,4]thiazine hydrochloride

mp: >250° C. IR (Nujol). 3150, 1665 cm⁻¹ ; (+) APCI MASS: 214 (M+H)⁺ ;NMR (DMSO-d₆, δ): 3.66 (2H, s), 7.72 (1H, s), 9.37 (4H, br s), 11.10(1H, br s).

The following compounds were obtained according to a similar manner tothat of Example 3.

EXAMPLE 11-1)

6-Amidino-2,3-dihydro-1-(2-hydroxyethyl)-2-oxo-1H-thieno[2,3-b][1,4]thiazinetrifluoroacetate

IR (Nujol): 1625 cm⁻¹ ; (+) APCI MASS: 258 (M+H)⁺ ; NMR (DMSO-d₆, δ):3.5-3.7 (2H, m), 3.74 (2H, s), 3.8-4.0 (2H, m), 8.09 (1H, s), 9.18 and9.30 (4H, each s).

EXAMPLE 11-2)

6-Amidino-1-(n-butylcarbamoylmethyl)-2,3-dihydro-2-oxo-1H-thieno[2,3-b][1,4]thiazinehydrochloride

IR (Nujol): 1650, 1560, 1500 cm⁻¹ ; NMR (DMSO-d₆, δ): 0.8-0.9 (3H, m),1.2-1.5 (4H, m), 0.3.0-3.2 (2H, m), 3.79 (2H, s), 4.42 (2H, s), 8.03(1H, s), 8.19 (1H, t, J=5.4 Hz), 9.23 (4H, br s).

EXAMPLE 11-3)

6-Amidino-1-(2,2,2-trifluoroethylcarbamoylmethyl)-2,3-dihydro-2-oxo-1H-thieno[2,3-b][1,4]thiazinehydrochloride

IR (Nujol): 3300, 3100, 1640, 1570, 1510 cm⁻¹ ; (+) APCI MASS: 353(M+H)⁺ ; NMR (DMSO-d₆, δ): 3.80 (2H, s), 3.8-4.1 (2H, m), 4.53 (2H, s),8.00 (1H, s), 8.9-9.1 (1H, m), 9.22 (4H, br s).

EXAMPLE 11-4)

2-Amidino-1-(3-ethoxycarbonylpropyl)-2,3-dihydro-2-oxo-1H-thieno2,3-b][1,4]thiazinehydrochloride

IR (Nujol): 3350, 1720, 1655, 1630, 1570 cm⁻¹ ; (+) APCI MASS: 328(M+H)⁺ ; NMR (DMSO-d₆, δ): 1.17 (3H, t, J=7.1 Hz), 1.7-1.9 (2H, m), 2.35(2H, t, J=7.5 Hz), 3.75 (2H, s), 3.89 (2H, t, J=7.0 Hz), 4.04 (2H, q,J=7.1 Hz), 8.26 (1H, s), 9.29 (4H, br s).

EXAMPLE 11-5)

6-Amidino-2,3-dihydro-1-(3,4-methylenedioxyphenylcarbamoylmethyl)-2-oxo-1H-thieno[2,3-b][1,4]thiazinehydrochloride

IR (Nujol): 1660, 1565 cm⁻¹ ; NMR (DMSO-d₆, δ): 3.82 (2H, s), 4.66 (2H,s), 5.98 (2H, s), 6.85 (1H, d, J=8.4 Hz), 7.02 (1H, d, J=8.4 Hz), 7.32(1H, s), 8.19 (1H, s), 9.26 (4H, br s), 10.48 (1H, s).

EXAMPLE 11-6)

6-Amidino-1-n-butyl-2,3-dihydro-2-oxo-1H-thieno[2,3-b][4-] thiazinehydrochloride

mp: 213-214 ° C.

IR (Nujol): 1640, 1570 cm⁻¹ ; (+) APCI MASS: 270 (M+H)⁺ ; NMR (DMSO-d₆,δ): 0.89 (3H, t, J=7.2 Hz), 1.2-1.6 (4H, m), 3.74 (2H, s), 3.8-4.0 (2H,m), 8.25 (1H, s), 9.31 (4H, br s); Elemental Analysis for C₁₁ H₁₆ ClN₃OS₂.0.75H₂ O; Calcd.: C; 41.-37, H; 5.52, N; 13.16; Found: C; 41.42, H;5.40, N; 13.22.

The following compound was synthesized according to the similar mannerto that of Example 1.

EXAMPLE 12

6-Amidino-2,3-dihydro-1-(2-methylthioethyl)-2-oxothieno[2,3-b][1,4]thiazinehydrochloride

IR (KBr): 1664, 1594 cm⁻¹ ; NMR (DMSO-d₆, δ): 2.15 (3H, s), 2.71 (2H, t,J=7.4), 3.86 (2H, s), 4.13 (2H, t, J=7.4 Hz), 7.50 (1H, br s), 7.97 (1H,s), 8.15 (1H, br s), 9.13 (1H, br s).

EXAMPLE 13-1)

6-Ethoxycarbonyl-2-(1-ethoxy-1-iminomethyl)-4,5,6,7-tetrahydrobenzo[b]thiophenehydrochloride (1.51 g), 2.7 N ethanol solution of ammonia (1.41 ml) andEtOH (5 ml) was stirred at reflux for 4 hours. After evaporation, theresulting oil was purified by chromatography on silica gel (CHCl₃ -MeOHas eluent), and subsequently washed with Et₂ O to give2-amidino-6-ethoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophenehydrochloride (1.20 g).

mp: 155-157° C. IR (KBr): 3101 (br), 1726, 1660, 1573, 1513 cm⁻¹ ; APCIMASS: 253(M+H of free); NMR (DMSO-d₆, δ): 1.20 (3H, t, J=7.1 Hz), 1.8(1H, m), 2.1 (1H, m), 2.67 (2H, t, J=5.8 Hz), 2.8-3.2 (3H, m), 4.11 (2H,q, J=7.1 Hz), 7.81 (1H, s), 9.02 and 9.22 (4H, both br s).

EXAMPLE 13-2)

A mixture of2-amidino-6-ethoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophenehydrochloride (1.15 g), and 6 N HCl (10 ml) was stirred at 70° C. for 9hours. The resulting precipitate was washed with Et₂ O to give2-amidino-6-carboxy-4,3,6,7-tetrahydrobenzo[b]thiophene hydrochloride(0.96 g).

mp: >250° C. IR (KBr): 3342, 3122, 2879, 1700, 1664, 1573, 1515 cm⁻¹ ;APCI MASS: 225 (M+H of free); NMR (DMSO-d₆, δ): 1.83 (1H, m), 2.10 (1H,m), 2.6-3.2 (5H, m), 7.82 (1H, s), 9.06 and 9.24 (4H, both br s).

EXAMPLE 13-3)

To a mixture of 2-amidino-6-carboxy-4,5,6,7-tetrahydrobenzo[b]thiophenehydrochloride (0.91 g), water (20 ml), and dioxane (40 ml) was dropwiseadded di-tert-butyl dicarbonate (0.88 ml) maintaining to pH; 9.5-10, andwas stirred at r.t. for 2 hours. The reaction mixture was adjusted topH; 4 with 6 N HCl, and was extracted with AcOEt. The separated organiclayer was washed with water, and dried over MgSO₄, and evaporated. Theresulting precipitate was washed with n-hexane to give 2-(N¹-tert-butoxycarbonylamidino)-6-carboxy-4,5,6,7-tetrahydrobenzo[b]thiophene(0.86 g).

NMR (DMSO-d₆, δ): 1.42 (9H, s), 1.83 1(1H, m), 2.10 (1H, m), 2.6-3.2(5H, m), 7.66 (1H, s), 8.91 (3H, br s).

EXAMPLE 13-4)

To a mixture of 2-(N¹-tert-butoxycarbonylamidino)-6-carboxy-4,5,6,7-tetrahydrobenzo[b]thiophene(0.40 g), CH₂ CH₂ (10 m), and dimethylformamide (DMF) (2 ml) was addedtriethylamine (0.17 ml) at r.t., and thenO-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate(0.40 g) was added thereto. The reaction mixture was stirred at r.t. for15 minutes. To the reaction mixture were added N,O-dimethylhydroxyaminehydrochloride (0.13 g) and triethylamine (0.19 ml), and the mixture wasstirred at r.t. for 1 hour. After removal of solvents by nitrogen flow,the reaction mixture was added into a mixture of AcOEt and water. Theseparated organic layer was washed with water, and brine, and dried overMgSO₄. After evaporation of the filtrate, the resulting precipitate waswashed with isopropyl ether to give 2-(N¹-tert-butoxycarbonylamidino)-6-(N-methyl-N-methoxycarbamoyl)-4,5,6,7-tetrahydrobenzo[b]thiophenewhich was used in the following reaction without further purification.

EXAMPLE 13-5)

A mixture of crude 2-(N¹-tert-butoxycarbonylamidino)-6-(N-methyl-N-methoxycarbamoyl)-4,5,6,7-tetrahydrobenzo[b]-thiophene(0.05 g), water (0.06 ml), and trifluoroacetic acid (TFA) (0.6 ml) wasstirred at r.t. for 2 hours. After removal of solvent by nitrogen flow,the resulting precipitate was washed with Et₂ O to give2-amidino-6-(N-methyl-N-methoxycarbamoyl)-4,5,6,7-tetrahydrobenzo[b]thiophenetrifluoroacetate (40.2 mg).

IR (KBr): 3301, 3085, 1670, 1577, 1515 cm⁻¹ ; APCI MASS: 268 (M+H offree); NMR (DMSO-d₆, δ): 1.83 (1H, m), 2.10 (1H, m), 2.6-3.2 (5H, m),3.15 (3H, s), 3.71 (3H, s), 7.84 (1H, s), 8.89 and 9.11 (4H, both br s).

EXAMPLE 13-6)

To a mixture of 2-(N¹-tert-butoxycarbonylamidino)-6-(N-methyl-N-methoxycarbamoyl)-4,5,6,7-tetrahydrobenzo[b]-thiophene(0.37 g), Et₂ O (10 ml), and tetrahydrofuran (THF) (2 ml) was addedlithium aluminum hydride (76.4 mg) at 0° C. under nitrogen atmosphere.The reaction mixture was stirred under the same conditions for 30minutes. To the reaction mixture was added a saturated aqueous solutionof ammonium hydrochloride to quench the reaction. The reaction mixturewas added into a mixture of AcOEt and water. After removal of resultinginsoluble precipitates by filtration, the separated organic layer waswashed with water, and brine, and dried over MgSO₄. After evaporation ofthe filtrate, the resulting precipitate was washed with isopropyl etherto give 2-(N¹-tert-butoxycarbonylamidino)-6-formyl-4,5,6,7-tetrahydrobenzo[b]thiophene(0.26 g), which was used in the following next reaction without furtherpurification.

The following compound was obtained according to a similar manner tothat of Example 13-5).

EXAMPLE 13-7)

2-Amidino-6-formyl-4,5,6,7-tetrahydrobenzo[b]thiophene trifluoroacetate

mp: 191-194° C. IR (KBr): 3083, 1672, 1579, 1517 cm⁻¹ ; MASS (z/e): 209(M+H)⁺ of free; NMR (DMSO-d₆, δ): 1.80 (1H, m), 2.10 (1H, m), 2.67 (2H,t, J=6.2 Hz), 2.6-3.2 (3H, m), 7.73 (1H, s), 8.95 and 9.11 (4H, both brs), 9.71 (1H, s).

EXAMPLE 14-1)

The following compound was obtained according to a similar manner tothat of Example 3.

6-Amidino-2,3-dihydro-1-(ethoxycarbonylacetyl)thieno[2,3-b][1,4]thiazinehydrochloride

(+) APCI MASS: 314 (M+H)⁺ ; NMR (DMSO-d₆, δ): 1.1-1.3 (3H, m), 3.3-3.5(2H, m), 3.83 (2H, s), 3.9-4.2 (4H, m), 8.51 (1H, s), 9.17 (4H, s).

EXAMPLE 14-2)

The following compound was obtained according to a similar manner tothat of Example 9-2).

6-Amidino-1-carboxyacetyl-2,3-dihydrothieno[2,3-b][1,4]thiazinehydrochloride

IR (Nujol): 1700, 1655, 1625 cm⁻¹ ; NMR (DMSO-d₆, δ): 3.0-3.2 (2H, m),3.25 (2H, s), 3.4-3.6 (2H, m)l, 7.51 (1H, s), 8.97 and 9.14 (4H, eachs).

EXAMPLE 15

The following compound was obtained according to a similar manner tothat of Example 3.

6-Amidino-1-benzoyl-2,3-dihydrothieno[2,3-b][1,4]-thiazine hydrochloride

(+) APCI MASS: 304 (M+H)⁺ ; NMR (DMSO-d₆, δ): 3.3-3.5 (2H, m), 3.9-4.1(2H, m), 7.53 (5H, s), 8.29 (1H, s), 9.19 (4H, s).

EXAMPLE 16

The following compound was obtained according to a similar manner tothat of Example 3.

1-Acetyl-6-amidino-2,3-dihydrothieno[2,3-b][1,4]thiazine hydrochloride

(+) APCI MASS: 242 (M+H)⁺ ; NMR (DMSO-d₆, δ): 2.25 (3H, s), 3.3-3.4 (2H,m), 3.9-4.1 (2H, m), 8.44 (1H, s), 9.24 (4H, br s).

EXAMPLE 17-1)

The following compound was obtained according to a similar manner tothat of Example 1, which was used in the next reaction without furtherpurification.

6-Amidino-2,3-dihydro-1-ethylthieno[2,3-b][1,4]thiazine hydrochloride

EXAMPLE 17-2)

The following compound was obtained according to a similar manner tothat of Example 13-3).

6- (N¹-tert-Butoxycarbonylamidino)-2,3-dihydro-1-ethylthieno[2,3-b][1,4]thiazine

(+) APCI MASS: 328 (M+H)⁺ ; NMR (DMSO-d₆, δ): 1.06 (3H, t, J=7.0 Hz),1.42 (9H, s), 3.0-3.2 (2H, m), 3.25 (2H, q, J=7.0 Hz), 3.4-3.5 (2H, m),7.73 (1H, s), 8.87 (2H, br s).

EXAMPLE 17-3)

A solution of 6-(N¹-tert-butoxycarbonylamidino)-2,3-dihydro-1-ethylthieno[2,3-b][1,4]thiazine(0.51 g) in trifluoroacetic acid (4.5 ml) and water (0.5 ml) was stirredfor 72 hours at room temperature. The solvent was evaporated in vacuoand the residue was pulverized from diethyl ether to give6-amidino-2,3-dihydro-1-ethylthieno[[2,3-b][1,4]thiazinetrifluoroacetate (0.50 g).

(+) APCI MASS: 228 (M+H)⁺ ; NMR (DMSO-d₆, δ): 1.0-1.2 (3H, m), 3.1-3.6(6H, m), 7.74 (1H, s), 9.02 (4H, br s).

What is claimed is:
 1. A compound of the formula ##STR13## in which R¹is hydrogen, lower alkyl, optionally substituted ar(lower)alkyl,cyclo(lower)alkyl(lower)alkyl, protected carboxy(lower)alkyl,carboxy)lower)alkyl, hydroxy(lower)alkyl, optionally substituted loweralkylcarbamoyl(lower)alkyl, lower alkylthio(lower)alkyl,carboxy(lower)alkanoyl, protected carboxy(lower)alkanoyl, aroyl, loweralkanoyl, or optionally substituted arylcarbamoyl(lower)alkyl,R² ishydrogen, carboxy, protected carboxy, formyl orN-(lower)alkyl-N-(lower)alkoxycarbamoyl, R³ is hydrogen oramidino-protective group, A is lower alkylene or carbonyl, X is##STR14## Y is --S-- or --SO₂ --, and Z is --S-- or --O--, orpharmaceutically acceptable salts thereof.
 2. The compound of claim 1,whereinR¹ is hydrogen; lower alkyl; ar(lower)alkyl optionallysubstituted by the group consisting of lower alkyl, lower alkoxy andlower alkylenedioxy; cyclo(lower)alkyl(lower)alkyl; loweralkoxycarbonyl(lower)alkyl; carboxy(lower)alkyl; hydroxy(lower)alkyl;lower alkylcarbamoyl(lower)alkyl optionally substituted by halogen;lower alkylthio(lower)alkyl; carboxy(lower)alkanoyl; loweralkoxycarbonyl(lower)alkanoyl; aroyl; lower alkanoyl; orarylcarbamoyl(lower)alkyl optionally substituted by the group consistingof lower alkyl, lower alkoxy and lower alkylenedioxy; R² is hydrogen,carboxy, lower alkoxycarbonyl, formyl, orN-(lower)alkyl-N-(lower)alkoxycarbamoyl, and R³ is hydrogen or loweralkoxycarbonyl.
 3. The compound of claim 2, whereinR¹ is hydrogen; loweralkyl; ar(lower)alkyl optionally substituted by the group consisting oflower alkyl, lower alkoxy and lower alkylenedioxy;cyclo(lower)alkyl(lower)alkyl; lower alkoxycarbonyl(lower)alkyl;carboxy(lower)alkyl; hydroxy(lower)alkyl; loweralkylcarbamoyl(lower)alkyl optionally substituted by halogen; loweralkylthio(lower)alkyl; carboxy(lower)alkanoyl; protectedcarboxy(lower)alkanoyl; aroyl; lower alkanoyl; orarylcarbamoyl(lower)alkyl optionally substituted by the group consistingof lower alkyl, lower alkoxy and lower alkylenedioxy; X is ##STR15## Yis --S-- or --SO₂ --, and Z is --S--.
 4. A pharmaceutical compositionwhich comprises, as an active ingredient, a compound of claim 1 or apharmaceutically acceptable salt thereof in admixture withpharmaceutially acceptable carriers or excipients.
 5. A method fortreatment of diseases initiated by urokinase which comprisesadministering an effective amount of a compound of claim 1 or apharmaceutically acceptable salt thereof to a human being or an animal.6. A process for the preparation of a compound of claim 1,comprising:converting the ester moiety of the compound of formula (II)##STR16## in which R¹, R², A, X, Y and Z are as defined in claim 1 andR⁴ is an ester residue, or a salt thereof, to the amidino moiety therebyproducing a compound of formula (I-a): ##STR17## or a salt thereof.